Benzylic oxindole pyrimidines

ABSTRACT

The present invention encompasses compounds of general formula (I) 
                         
wherein the groups R 5  to R 10 , A, L 1 , B, m and p are defined as in claim  1 , which are suitable for the treatment of diseases characterized by excessive or abnormal cell proliferation, pharmaceutical preparations which contain such compounds and their use as medicaments.

The present invention relates to new benzylic oxindolepyrimidines of general formula (I)

wherein the groups R⁵ to R¹⁰, A, L¹, B, m and p have the meanings given in the claims and specification, which are suitable for the treatment of diseases characterised by excessive or abnormal cell proliferation, pharmaceutical preparations which contain such compounds and their use as medicaments. The compounds according to the invention display an inhibitory effect on the phosphorylation activity of the IGF-1 receptor located in cell membranes.

BACKGROUND TO THE INVENTION

WO 2006/021544 describes diamino-substituted pyrimidines that carry bi- and tricyclic substituents in position 4 of the pyrimidine ring, as PLK1 inhibitors.

WO 2004/080980 describes diamino-substituted pyrimidines that carry inter alia bicyclic substituents in position 4 of the pyrimidine ring, as IGF-1R inhibitors.

The aim of the present invention is to indicate new compounds which can be used for the prevention and/or treatment of diseases characterised by excessive or abnormal cell proliferation. The compounds according to the invention are characterised by a powerful inhibitory effect on the phosphorylation activity of the IGF-1 receptor located in cell membranes and a potent efficacy against tumour cells, e.g. glioblastoma cells, which is mediated through the inhibition of phosphorylation of the receptor. In addition to the inhibitory effect and cell activity the compounds have good solubility and good PK properties and good selectivity over other kinases (Invitrogen panel).

The insulin-like growth factor (IGF) and insulin signalling network is a highly conserved and essential pathway involved in biological processes including growth, metabolism and homeostasis. In addition, deregulated signalling via this network can enhance tumorigenesis and metastasis of certain cancers.

The ligands IGF-1, IGF-2 and insulin are highly homologous and activate specific hetero or homodimers of the IGF-1R and IR. Following ligand binding, the IGF-1R and IR undergo autophosphorylation mediated via the receptor tyrosine kinase domains. The phosphorylated receptors activate the canonical Ras-Raf-MEK-ERK1/2 and PI3K-PDK1-Akt intracellular signaling cascades, which leads to cell proliferation and survival. In addition, activation of the IR by insulin stimulates the uptake of glucose and storage of glycogen in metabolic tissues such as the liver, adipose and muscle.

Published research articles as well as medical and epidemiological investigations have identified a strong correlation between expression of the IGF-1R and IR and ligands for these receptors in tumor development and progression. Developing a small molecule competitive inhibitor of the ATP-binding pocket of the IGF-1R and IR as a means of blocking growth and survival signaling cascades in cancer is therefore desirable. The anticipated clinical benefit of blocking such an interaction would be to reduce tumor growth rate and potentially sensitize tumors to cytotoxic agents or targeted therapies.

DETAILED DESCRIPTION OF THE INVENTION

Surprisingly it has been found that compounds of general formula (I), wherein the groups R⁵ to R¹⁰, A, L¹, B, m and p have the meanings stated hereinafter, act as inhibitors of receptors that are involved in controlling cell proliferation. Thus, the compounds according to the invention may be used for example for the treatment of diseases associated with the activity of these receptors and characterised by excessive or abnormal cell proliferation.

The present invention therefore relates to compounds of general formula (I)

wherein (A0) R⁵ is selected from among trifluoromethyl and halogen; (B0) R⁶, R⁷ and R⁸ are each independently selected from among hydrogen and C₁₋₄alkyl or R⁶ and R⁷ together with the carbon atom to which they bond form a saturated, 3-5 membered hydrocarbon ring; (C0) ring system A is selected from among C₆₋₁₀aryl, 3-14 membered heterocyclyl and 5-12 membered heteroaryl; (D0) each R⁹ is independently selected in each case from among C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, halogen and —CN; m denotes 0, 1, 2 or 3; (E0) L¹ is selected from among a bond, —(CH₂)_(n)—O, —(CH₂)_(n)—NH, —(CH₂)_(n)—NH—C(O), —(CH₂)_(n)—C(O)—NH, —(CH₂)_(n)— and —(CH₂)_(n)—C(O), while in the present nomenclature the linker group L¹ on the right binds to the ring system A; n denotes 0, 1, 2 or 3; (F0) ring system B is selected from among 4-10 membered, saturated or unsaturated heterocyclyl and phenyl; (G0) each R¹⁰ is independently selected in each case from among R^(a) and R^(b); p denotes 0, 1, 2 or 3; each R^(a) independently denotes a group optionally substituted by one or more identical or different R^(b) and/or R^(c) selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl; each R^(b) is independently selected in each case from among —OR^(c), —SR^(c), —NR^(c)R^(c), halogen, —CN, —NO₂, —C(O)R^(c), —C(O)OR^(c), —C(O)NR^(c)R^(c), —C(NR^(f))NR^(c)R^(c), —OC(O)R^(c), —OC(O)OR^(c), —S(O)₂R^(c), —S(O)₂NR^(c)R^(c), —NR^(f)C(O)R^(c), —NR^(f)C(O)OR^(c), —NR^(f)C(O)NR^(c)R^(c), —NR¹C(NR^(f))NR^(c)R^(c) and —NR^(f)S(O)₂R^(c), as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems; each R^(c) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(d) and/or R^(e) selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl; each R^(d) is independently selected in each case from among —OR^(e), —SR^(e), —NR^(e)R^(e), halogen, —CN, —NO₂, —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(e)R^(e), —C(NR^(f))NR^(e)R^(e), —OC(O)R^(e), —OC(O)OR^(e), —S(O)₂R^(e), —S(O)₂NR^(e)R^(e), —NR^(f)C(O)R^(e), —NR^(f)C(O)OR^(e), —NR^(f)C(O)NR^(e)R^(e), —NR^(f)C(NR^(f))NR^(e)R^(e) and —NR^(f)S(O)₂R^(e), as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems; each R^(e) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(f) selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl, and

each R^(f) is independently selected in each case from among hydrogen and C₁₋₆alkyl,

while the compounds (I) may optionally also occur in the form of their tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or as the respective salts of all the above-mentioned forms.

The present invention further relates to compounds of general formula (I)

wherein (A0) R⁵ is selected from among trifluoromethyl and halogen; (B0) R⁶, R⁷ and R⁸ are independently selected in each case from among hydrogen and C₁₋₄alkyl or R⁶ and R⁷ together with the carbon atom to which they bond forms a saturated, 3-5 membered hydrocarbon ring; (C0) ring system A is selected from among C₆₋₁₀aryl and 5-12 membered heteroaryl; (D0) each R⁹ is independently selected in each case from among C₁₋₆alkyl, C₁₋₆alkoxy, halogen and —CN; m denotes 0, 1, 2 or 3; (E0) L¹ is selected from among a bond, —(CH₂)_(n)—O, —(CH₂)_(n)—NH, —(CH₂)_(n)—NH—C(O), —(CH₂)_(n)—C(O)—NH, —(CH₂)_(n)— and —(CH₂)_(n)—C(O), while in the present nomenclature the linker group L¹ on the right binds to the ring system A; n denotes 0, 1, 2 or 3; (F0) ring system B is selected from among 4-10 membered, saturated or unsaturated heterocyclyl and phenyl; (G0) each R¹⁰ is independently selected in each case from among R^(a) and R^(b); p denotes 0, 1, 2 or 3; each R^(a) independently denotes a group optionally substituted by one or more identical or different R^(b) and/or R^(c) selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl; each R^(b) is independently selected in each case from among —OR^(c), —SR^(c), —NR^(c)R^(c), halogen, —CN, —NO₂, —C(O)R^(c), —C(O)OR^(c), —C(O)NR^(c)R^(c), —C(NR^(f))NR^(c)R^(c), —OC(O)R^(c), —OC(O)OR^(c), —S(O)₂R^(c), —S(O)₂NR^(c)R^(c), —NR^(f)C(O)R^(c), —NR^(f)C(O)OR^(c), —NR^(f)C(O)NR^(c)R^(c), —NR^(f)C(NR^(f))NR^(c)R^(c) and —NR^(f)S(O)₂R^(c), as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems; each R^(c) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(d) and/or R^(e) selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl; each R^(d) is independently selected in each case from among —OR^(e), —SR^(e), —NR^(e)R^(e), halogen, —CN, —NO₂, —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(e)R^(e), —C(NR^(f))NR^(e)R^(e), —OC(O)R^(e), —OC(O)OR^(e), —S(O)₂R^(e), —S(O)₂NR^(e)R^(e), —NR^(f)C(O)R^(e), —NR^(f)C(O)OR^(e), —NR^(f)C(O)NR^(e)R^(e), —NR^(f)C(NR^(f))NR^(e)R^(e) and —NR^(f)S(O)₂R^(e), as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems; each R^(e) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(f) selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl, and each R^(f) is independently selected in each case from among hydrogen and C₁₋₆alkyl, while the compounds (I) may optionally also occur in the form of their tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or as the respective salts of all the above-mentioned forms.

In one aspect (A1) the invention relates to compounds (I), wherein

R⁵ denotes trifluoromethyl.

In one aspect (A2) the invention relates to compounds (I), wherein

R⁵ denotes chlorine.

In one aspect (A3) the invention relates to compounds (I), wherein

R⁵ denotes bromine.

In another aspect (B1) the invention relates to compounds (I), wherein

R⁶ and R⁷ in each case denote methyl and R⁸ denotes hydrogen.

In another aspect (B2) the invention relates to compounds (I), wherein

R⁶, R⁷ and R⁸ in each case denote hydrogen.

In another aspect (B3) the invention relates to compounds (I), wherein

R⁶ and R⁷ together with the carbon atom to which they bond form a cyclopropyl ring and

R⁸ denotes hydrogen.

In another aspect (C1) the invention relates to compounds (I), wherein

ring system A is selected from among phenyl and 5-6 membered heteroaryl.

In another aspect (C2) the invention relates to compounds (I), wherein

ring system A is a phenyl.

In another aspect (C3) the invention relates to compounds (I), wherein

ring system A is a 5-6 membered, nitrogen-containing heteroaryl.

In another aspect (C4) the invention relates to compounds (I), wherein

ring system A is a pyridyl or pyrazolyl.

In another aspect (D1) the invention relates to compounds (I) wherein

m has the value 0.

In another aspect (D2) the invention relates to compounds (I), wherein

m has the value 1 or 2 and

R⁹ is selected from among halogen, C₁₋₄alkyl and C₁₋₄alkoxy.

In another aspect (D3) the invention relates to compounds (I), wherein

m has the value 1 or 2 and

R⁹ is selected from among C₁₋₄alkyl and C₁₋₄alkoxy.

In another aspect (D4) the invention relates to compounds (I), wherein

m has the value 1 or 2 and

R⁹ is selected from among methyl, ethyl, methoxy and ethoxy.

In another aspect (CD1) the invention relates to compounds (I), wherein

ring system A and the m groups R⁹ together denote

R^(9a) is selected from among hydrogen, C₁₋₄alkyl and C₁₋₄alkoxy and R^(9b) is selected from among hydrogen and C₁₋₄alkyl.

In another aspect (CD2) the invention relates to compounds (I), wherein

ring system A and the m groups R⁹ together denote

R^(9a) is selected from among C₁₋₄alkyl and C₁₋₄alkoxy and R^(9b) is selected from among hydrogen and C₁₋₄alkyl.

In another aspect (CD3) the invention relates to compounds (I), wherein

ring system A and the m groups R⁹ together denote

R^(9a) is selected from among hydrogen, methyl, ethyl, methoxy and ethoxy and R^(9b) is selected from among hydrogen, methyl and ethyl.

In another aspect (CD4) the invention relates to compounds (I), wherein

ring system A and the m groups R⁹ together denote

R^(9a) is selected from among methyl, ethyl, methoxy and ethoxy and R^(9b) is selected from among hydrogen, methyl and ethyl.

In another aspect (CD5) the invention relates to compounds (I), wherein

ring system A and the m groups R⁹ together denote

In another aspect (E1) the invention relates to compounds (I), wherein

L¹ is selected from among a bond, —(CH₂)₂—O, —NH—C(O), —C(O)—NH— and —C(O), while in the present nomenclature the linker group L¹ on the right binds to the ring system A.

In another aspect (E2) the invention relates to compounds (I), wherein

L¹ corresponds to a bond.

In another aspect (E3) the invention relates to compounds (I), wherein

L¹ is selected from among —(CH₂)₂—O, —NH—C(O)— and —C(O)—.

In another aspect (F1) the invention relates to compounds (I), wherein

ring system B is a 4-10 membered, saturated or unsaturated heterocyclyl.

In another aspect (F2) the invention relates to compounds (I), wherein

ring system B is a 5-7 membered, saturated and nitrogen-containing heterocyclyl.

In another aspect (F3) the invention relates to compounds (I), wherein

ring system B is selected from among piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl and 2,5-diaza-bicyclo[2,2,1]heptyl.

In another aspect (G1) the invention relates to compounds (I), wherein

p has the value 0.

In another aspect (G2) the invention relates to compounds (I), wherein

p has the value 1 or 2;

each R¹⁰ is independently selected in each case from among R^(a) and R^(b);

each R^(a) independently denotes a group optionally substituted by one or more identical or different R^(b) and/or R^(c) selected from among C₁₋₆alkyl, C₃₋₁₀cycloalkyl and 3-14 membered heterocyclyl;

each R^(b) is independently selected in each case from among —OR^(c), —NR^(c)R^(c), halogen, —CN, —C(O)R^(c), —C(O)OR^(c), —C(O)NR^(c)R^(c), —S(O)₂R^(c) and —S(O)₂NR^(c)R^(c), as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems;

each R^(c) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(d) and/or R^(e) selected from among C₁₋₆alkyl, C₃₋₁₀cycloalkyl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl;

each R^(d) is independently selected in each case from among —OR^(e), —NR^(e)R^(e), —CN, —C(O)R^(e), —C(O)OR^(e) and —NR^(f)C(O)OR^(e), as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems;

each R^(e) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(f) selected from among C₁₋₆alkyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl, and

each R^(f) is independently selected in each case from among hydrogen and C₁₋₆alkyl.

In another aspect (G3) the invention relates to compounds (I), wherein

p has the value 1 or 2,

each R¹⁰ is independently selected in each case from among R^(a) and R^(b);

each R^(a) independently denotes a group optionally substituted by one or more identical or different R^(b) and/or R^(c) selected from among C₁₋₆alkyl, C₃₋₆cycloalkyl and 4-7 membered heterocyclyl;

each R^(b) is independently selected in each case from among —OR^(c), —NR^(c)R^(c), halogen, —CN, —C(O)R^(c), —C(O)OR^(c), —C(O)NR^(c)R^(c), —S(O)₂R^(c) and —S(O)₂NR^(c)R^(c), as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems;

each R^(c) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(d) and/or R^(e) selected from among C₁₋₆alkyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocyclyl;

each R^(d) is independently selected in each case from among —OR^(e), —NR^(e)R^(e), —CN, —C(O)R^(e), —C(O)OR^(e) and —NR^(f)C(O)OR^(e), as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems;

each R^(e) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(f) selected from among C₁₋₆alkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocyclyl, and

each R^(f) is independently selected in each case from among hydrogen and C₁₋₆alkyl.

In another aspect (FG1) the invention relates to compounds (I), wherein

ring system B and the p groups R¹⁰ together denote

each R¹⁰ is independently selected in each case from among R^(a) and R^(b); each R^(a) independently denotes a group optionally substituted by one or more identical or different R^(b) and/or R^(c) selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl; each R^(b) is independently selected in each case from among —OR^(c), —SR^(c), —NR^(c)R^(c), halogen, —CN, —NO₂, —C(O)R^(c), —C(O)OR^(c), —C(O)NR^(c)R^(c), —C(NR^(f))NR^(c)R^(c), —OC(O)R^(c), —OC(O)OR^(c), S(O)₂R^(c), —S(O)₂NR^(c)R^(c), —NR^(f)C(O)R^(c), —NR^(f)C(O)OR^(c), —NR^(f)C(O)NR^(c)R^(c), —NR^(f)C(NR^(f))NR^(c)R^(c) and —NR^(f)S(O)₂R^(c), as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems; each R^(c) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(d) and/or R^(e) selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl; each R^(d) is independently selected in each case from among —OR^(e), —SR^(e), —NR^(e)R^(e), halogen, —CN, —NO₂, —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(e)R^(e), —C(NR^(f))NR^(e)R^(e), —OC(O)R^(e), —OC(O)OR^(e), —S(O)₂R^(e), —S(O)₂NR^(e)R^(e), —NR^(f)C(O)R^(e), —NR^(f)C(O)OR^(e), —NR^(f)C(O)NR^(e)R^(e), —NR^(f)C(NR^(f))NR^(e)R^(e) and —NR^(f)S(O)₂R^(e), as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems; each R^(e) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(f) selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl, and each R^(f) is independently selected in each case from among hydrogen and C₁₋₆alkyl.

In another aspect (FG2) the invention relates to compounds (I), wherein

ring system B and the p groups R¹⁰ together denote

each R¹⁰ is independently selected in each case from among R^(a) and R^(b); each R^(a) independently denotes a group optionally substituted by one or more identical or different R^(b) and/or R^(c) selected from among C₁₋₆alkyl, C₃₋₁₀cycloalkyl and 3-14 membered heterocyclyl; each R^(b) is independently selected in each case from among —OR^(c), —NR^(c)R^(c), halogen, —CN, —C(O)R^(c), —C(O)OR^(c), —C(O)NR^(c)R^(c), —S(O)₂R^(c) and —S(O)₂NR^(c)R^(c), as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems; each R^(c) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(d) and/or R^(e) selected from among C₁₋₆alkyl, C₃₋₁₀cycloalkyl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl;

each R^(d) is independently selected in each case from among —OR^(e), —NR^(e)R^(e), —CN, —C(O)R^(e), —C(O)OR^(e) and —NR^(f)C(O)OR^(e), as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems;

each R^(e) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(f) selected from among C₁₋₆alkyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl, and

each R^(f) is independently selected in each case from among hydrogen and C₁₋₆alkyl.

In another aspect (FG3) the invention relates to compounds (I), wherein ring system B and the p groups R¹⁰ together denote

each R¹⁰ is independently selected in each case from among R^(a) and R^(b); each R^(a) independently denotes a group optionally substituted by one or more identical or different R^(b) and/or R^(c) selected from among C₁₋₆alkyl, C₃₋₆cycloalkyl and 4-7 membered heterocyclyl; each R^(b) is independently selected in each case from among —OR^(c), —NR^(c)R^(c), halogen, —CN, —C(O)R^(c), —C(O)OR^(c), —C(O)NR^(c)R^(c), —S(O)₂R^(c) and —S(O)₂NR^(c)R^(c), as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems;

each R^(c) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(d) and/or R^(e) selected from among C₁₋₆alkyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocyclyl;

each R^(d) is independently selected in each case from among —OR^(e), —NR^(e)R^(e), —CN, —C(O)R^(e), —C(O)OR^(e) and —NR^(f)C(O)OR^(e), as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems;

each R^(e) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(f) selected from among C₁₋₆alkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocyclyl, and

each R^(f) is independently selected in each case from among hydrogen and C₁₋₆alkyl.

In another aspect (FG4) the invention relates to compounds (I), wherein

ring system B and the p groups R¹⁰ together denote

each R¹⁰ is independently selected in each case from among —C(O)—C₁₋₄alkyl, hydrogen, C₁₋₆alkyl (CN), C₁₋₆haloalkyl —C(O)—O—C₁₋₄alkyl, —COOH, (C₁₋₄alkyl)₂N—C₁₋₄alkylene-C(O), (C₁₋₄alkyl)NH—C₁₋₄alkylene-C(O), H₂N—C₁₋₄alkylene-C(O), HO—C₁₋₄alkylene-C(O), —C(O)—N(C₁₋₄alkyl)₂, —C(O)—NH(C₁₋₄alkyl), —C(O)NH₂, C₁₋₄alkyl-O—C₁₋₄alkylene-C(O), 4-6 membered heterocyclyl (optionally substituted by C₁₋₄alkyl, C₃₋₆cycloalkyl or 3-6 membered heterocyclyl), C₃₋₆cycloalkyl, C₃₋₆cycloalkyl-C₁₋₄alkyl, HO—C₂₋₄alkyl, C₁₋₄alkyl-O—C₂₋₄alkyl, HO—C₂₋₄haloalkyl, C₁₋₄alkyl-S(O)₂, C₁₋₄alkyl-NH—C(O)—C₁₋₄alkyl, H₂N—C(O)—C₁₋₄alkyl and C₁₋₄alkyl-S(O)₂—C₁₋₄alkyl

In another aspect (FG5) the invention relates to compounds (I), wherein

ring system B and the p groups R¹⁰ together denote

In another aspect (FG6) the invention relates to compounds (I), wherein

ring system B and the p groups R¹⁰ together denote

each R¹⁰ is independently selected in each case from among C₁₋₄alkyl-O—C₂₋₄alkylene-NH, C₁₋₄alkyl-O—C₂₋₄alkylene-N(C₁₋₄alkyl), HO—C₂₋₄alkylene-N(C₁₋₄alkyl), HO—C₂₋₄alkylene-NH, 4-6 membered heterocyclyl (optionally substituted by C₁₋₄alkyl, 3-6 membered heterocyclyl, halogen, —OH, —CN, C₁₋₄alkoxy, —N(C₁₋₄alkyl)₂ or C₃₋₆cycloalkyl), (C₁₋₄alkyl)₂N—C₂₋₄alkylene-N(C₁₋₄alkyl), (C₁₋₄alkyl)₂N—C₂₋₄alkylene-NH, —N(C₁₋₄alkyl)₂, —NH(C₁₋₄alkyl), C₁₋₄alkyl-NH—C(O)— and (C₁₋₄alkyl)₂N—C(O).

In another aspect the invention relates to compounds (I), wherein

p has the value 1.

All the above-mentioned structural aspects A1 to A3, B1 to B3, C1 to C4, D1 to D4, CD1 to CD5, E1 to E3, F1 to F3, G1 to G3 and FG1 to FG6 are preferred embodiments of the respective aspects A0, B0, C0, D0, CD0, E0, F0, G0 and FG0, wherein CD0 denotes the combination of C0 and D0 and FG0 denotes the combination of F0 and G0. The structural aspects A0 to A3, B0 to B3, C0 to C4, D0 to D4, CD0 to CD5, E0 to E3, F0 to F3, G0 to G3 and FG0 to FG6 with respect to different molecular parts of the compounds (I) according to the invention may be permutated with one another as desired to form ABCDEFG combinations, thus obtaining preferred compounds (I). Each ABCDEFG combination represents and defines individual embodiments or generic partial amounts of compounds A0B0C0D0E0F0G0 according to the invention. Every individual embodiment or partial quantity defined by this combination is expressly included in and a subject of the invention.

The present invention further relates to hydrates, solvates, polymorphs, metabolites, derivatives and prodrugs of compounds of general formula (I).

The present invention further relates to a pharmaceutically acceptable salt of a compound of general formula (I) with anorganic or organic acids or bases.

In another aspect the invention relates to compounds of general formula (I)—or the pharmaceutically acceptable salts thereof—as medicaments.

In another aspect the invention relates to compounds of general formula (I)—or the pharmaceutically acceptable salts thereof—for use in a method for treatment of the human or animal body.

In another aspect the invention relates to compounds of general formula (I)—or the pharmaceutically acceptable salts thereof—for use in the treatment and/or prevention of cancer, infections, inflammations and autoimmune diseases.

In another aspect the invention relates to compounds of general formula (I)—or the pharmaceutically acceptable salts thereof—for use in a method for treatment and/or prevention of cancer, infections, inflammations and autoimmune diseases in the human and animal body.

In another aspect the invention relates to the use of compounds of general formula (I)—or the pharmaceutically acceptable salts thereof—for preparing a pharmaceutical composition for the treatment and/or prevention of cancer, infections, inflammations and autoimmune diseases.

In another aspect the invention relates to compounds of general formula (I)—or the pharmaceutically acceptable salts thereof—for use in the treatment and/or prevention of cancer.

In another aspect the invention relates to the use of compounds of general formula (I)—or the pharmaceutically acceptable salts thereof—for preparing a pharmaceutical composition for the treatment and/or prevention of cancer.

In another aspect the invention relates to compounds of general formula (I)—or the pharmaceutically acceptable salts thereof—for use in a method for treatment and/or prevention of cancer in the human or animal body.

In another aspect the invention relates to compounds of general formula (I)—or the pharmaceutically acceptable salts thereof—for use in the treatment and/or prevention of hepatocellular carcinomas (HCC), non-small cell lung cancer (NSCLC), breast cancer and prostate cancer.

In another aspect the invention relates to the use of compounds of general formula (I)—or the pharmaceutically acceptable salts thereof—for preparing a pharmaceutical composition for the treatment and/or prevention of hepatocellular carcinomas (HCC), non-small cell lung cancer (NSCLC), breast cancer and prostate cancer.

In another aspect the invention relates to compounds of general formula (I)—or the pharmaceutically acceptable salts thereof—for use in the treatment and/or prevention of hepatocellular carcinomas (HCC) and non-small cell lung cancer (NSCLC).

In another aspect the invention relates to the use of compounds of general formula (I)—or the pharmaceutically acceptable salts thereof—for preparing a pharmaceutical composition for the treatment and/or prevention of hepatocellular carcinomas (HCC) and non-small cell lung cancer (NSCLC).

In another aspect the invention relates to a process for the treatment and/or prevention of cancer comprising administering a therapeutically effective amount of a compound of general formula (I)—or one of the pharmaceutically acceptable salts thereof—to a human being.

In another aspect the invention relates to a pharmaceutical preparation containing as active substance one or more compounds of general formula (I)—or the pharmaceutically acceptable salts thereof—optionally in combination with conventional excipients and/or carriers.

In another aspect the invention relates to a pharmaceutical preparation comprising a compound of general formula (I)—or one of the pharmaceutically acceptable salts thereof —and at least one other cytostatic or cytotoxic active substance, different from formula (I).

DEFINITIONS

Terms that are not specifically defined here have the meanings that are apparent to the skilled man in the light of the overall disclosure and the context as a whole.

As used herein, the following definitions apply, unless stated otherwise:

The use of the prefix C_(x-y), wherein x and y each represent a natural number (x<y), indicates that the chains or ring structure or combination of chains and ring structure as a whole, specified and mentioned in direct association, may consist of a maximum of y and a minimum of x carbon atoms.

The indication of the number of members in groups that contain one or more heteroatom(s) (heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl) relates to the total atomic number of all the ring members or chain members or the total of all the ring and chain members.

Alkyl denotes monovalent, saturated hydrocarbon chains, which may be present in both straight-chain (unbranched) and branched form. If an alkyl is substituted, the substitution may take place independently of one another, by mono- or polysubstitution in each case, on all the hydrogen-carrying carbon atoms.

The term “C₁₋₅-alkyl” includes for example H₃C—, H₃C—CH₂—, H₃C—CH₂—CH₂—, H₃C—CH(CH₃)—, H₃C—CH₂—CH₂—CH₂—, H₃C—CH₂—CH(CH₃)—, H₃C—CH(CH₃)—CH₂—, H₃C—C(CH₃)₂—, H₃C—CH₂—CH₂—CH₂—CH₂—, H₃C—CH₂—CH₂—CH(CH₃)—, H₃C—CH₂—CH(CH₃)—CH₂—, H₃C—CH(CH₃)—CH₂—CH₂—, H₃C—CH₂—C(CH₃)₂—, H₃C—C(CH₃)₂—CH₂—, H₃C—CH(CH₃)—CH(CH₃)— and H₃C—CH₂—CH(CH₂CH₃)—.

Further examples of alkyl are methyl (Me; —CH₃), ethyl (Et; —CH₂CH₃), 1-propyl (n-propyl; n-Pr; —CH₂CH₂CH₃), 2-propyl (i-Pr; iso-propyl; —CH(CH₃)₂), 1-butyl (n-butyl; n-Bu; —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (iso-butyl; i-Bu; —CH₂CH(CH₃)₂), 2-butyl (sec-butyl; sec-Bu; —CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (tert-butyl; t-Bu; —C(CH₃)₃), 1-pentyl (n-pentyl; —CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl (—CH(CH₂CH₃)₂), 3-methyl-1-butyl (iso-pentyl; —CH₂CH₂CH(CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl (—CH(CH₃)CH(CH₃)₂), 2,2-dimethyl-1-propyl (neo-pentyl; —CH₂C(CH₃)₃), 2-methyl-1-butyl (—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (n-hexyl; —CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl (—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)), 2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl (—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂), 3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl (—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂), 3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃), 2,3-dimethyl-1-butyl (—CH₂CH(CH₃)CH(CH₃)CH₃), 2,2-dimethyl-1-butyl (—CH₂C(CH₃)₂CH₂CH₃), 3,3-dimethyl-1-butyl (—CH₂CH₂C(CH₃)₃), 2-methyl-1-pentyl (—CH₂CH(CH₃)CH₂CH₂CH₃), 3-methyl-1-pentyl (—CH₂CH₂CH(CH₃)CH₂CH₃), 1-heptyl (n-heptyl), 2-methyl-1-hexyl, 3-methyl-1-hexyl, 2,2-dimethyl-1-pentyl, 2,3-dimethyl-1-pentyl, 2,4-dimethyl-1-pentyl, 3,3-dimethyl-1-pentyl, 2,2,3-trimethyl-1-butyl, 3-ethyl-1-pentyl, 1-octyl (n-octyl), 1-nonyl (n-nonyl); 1-decyl (n-decyl) etc.

By the terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl etc. without any further definition are meant saturated hydrocarbon groups with the corresponding number of carbon atoms, wherein all isomeric forms are included.

The above definition for alkyl also applies if alkyl is a part of another group such as for example C_(x-y)-alkylamino or C_(x-y)-alkyloxy.

The term alkylene can also be derived from alkyl. Alkylene is bivalent, unlike alkyl, and requires two binding partners. Formally, the second valency is produced by removing a hydrogen atom in an alkyl. Corresponding groups are for example —CH₃ and —CH₂, —CH₂CH₃ and —CH₂CH₂ or >CHCH₃ etc.

The term “C₁₋₄-alkylene” includes for example —(CH₂)—, —(CH₂—CH₂)—, —(CH(CH₃))—, —(CH₂—CH₂—CH₂)—, —(C(CH₃)₂)—, —(CH(CH₂CH₃))—, —(CH(CH₃)—CH₂)—, —(CH₂—CH(CH₃))—, —(CH₂—CH₂—CH₂—CH₂)—, —(CH₂—CH₂—CH(CH₃))—, —(CH(CH₃)—CH₂—CH₂)—, —(CH₂—CH(CH₃)—CH₂)—, —(CH₂—C(CH₃)₂)—, —(C(CH₃)₂—CH₂)—, —(CH(CH₃)—CH(CH₃))—, —(CH₂—CH(CH₂CH₃))—, —(CH(CH₂CH₃)—CH₂)—, —(CH(CH₂CH₂CH₃))—, —(CHCH(CH₃)₂)— and —C(CH₃)(CH₂CH₃)—.

Other examples of alkylene are methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene, pentylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene, hexylene etc.

By the generic terms propylene, butylene, pentylene, hexylene etc. without any further definition are meant all the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propylene includes 1-methylethylene and butylene includes 1-methylpropylene, 2-methylpropylene, 1,1-dimethylethylene and 1,2-dimethylethylene.

The above definition for alkylene also applies if alkylene is part of another group such as for example in HO—C_(x-y)-alkylenamino or H₂N—C_(x-y)-alkylenoxy.

Unlike alkyl, alkenyl consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together by a C—C double bond. If in an alkyl as hereinbefore defined having at least two carbon atoms, two hydrogen atoms on adjacent carbon atoms are formally removed and the free valencies are saturated to form a second bond, the corresponding alkenyl is formed.

Examples of alkenyl are vinyl (ethenyl), prop-1-enyl, allyl (prop-2-enyl), isopropenyl, but-1-enyl, but-2-enyl, but-3-enyl, 2-methyl-prop-2-enyl, 2-methyl-prop-1-enyl, 1-methyl-prop-2-enyl, 1-methyl-prop-1-enyl, 1-methylidenepropyl, pent-1-enyl, pent-2-enyl, pent-3-enyl, pent-4-enyl, 3-methyl-but-3-enyl, 3-methyl-but-2-enyl, 3-methyl-but-1-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl, 2,3-dimethyl-but-3-enyl, 2,3-dimethyl-but-2-enyl, 2-methylidene-3-methylbutyl, 2,3-dimethyl-but-1-enyl, hexa-1,3-dienyl, hexa-1,4-dienyl, penta-1,4-dienyl, penta-1,3-dienyl, buta-1,3-dienyl, 2,3-dimethylbuta-1,3-diene etc.

By the generic terms propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexa-dienyl, heptadienyl, octadienyl, nonadienyl, decadienyl etc. without any further definition are meant all the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propenyl includes prop-1-enyl and prop-2-enyl, butenyl includes but-1-enyl, but-2-enyl, but-3-enyl, 1-methyl-prop-1-enyl, 1-methyl-prop-2-enyl etc.

Alkenyl may optionally be present in the cis or trans or E or Z orientation with regard to the double bond(s).

The above definition for alkenyl also applies when alkenyl is part of another group such as for example in C_(x-y)-alkenylamino or C_(x-y)-alkenyloxy.

Unlike alkylene, alkenylene consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together by a C—C double bond. If in an alkylene as hereinbefore defined having at least two carbon atoms, two hydrogen atoms at adjacent carbon atoms are formally removed and the free valencies are saturated to form a second bond, the corresponding alkenylene is formed.

Examples of alkenylene are ethenylene, propenylene, 1-methylethenylene, butenylene, 1-methylpropenylene, 1,1-dimethylethenylene, 1,2-dimethylethenylene, pentenylene, 1,1-dimethylpropenylene, 2,2-dimethylpropenylene, 1,2-dimethylpropenylene, 1,3-dimethylpropenylene, hexenylene etc.

By the generic terms propenylene, butenylene, pentenylene, hexenylene etc. without any further definition are meant all the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propenylene includes 1-methylethenylene and butenylene includes 1-methylpropenylene, 2-methylpropenylene, 1,1-dimethylethenylene and 1,2-dimethylethenylene.

Alkenylene may optionally be present in the cis or trans or E or Z orientation with regard to the double bond(s).

The above definition for alkenylene also applies when alkenylene is a part of another group as in for example HO—C_(x-y)-alkenylenamino or H₂N—C_(x-y)-alkenylenoxy.

Unlike alkyl, alkenyl consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together by a C—C triple bond. If in an alkyl as hereinbefore defined having at least two carbon atoms, two hydrogen atoms in each case at adjacent carbon atoms are formally removed and the free valencies are saturated to form two further bonds, the corresponding alkynyl is formed.

Examples of alkynyl are ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, 1-methyl-prop-2-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, 3-methyl-but-1-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl etc.

By the generic terms propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl etc. without any further definition are meant all the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propynyl includes prop-1-ynyl and prop-2-ynyl, butynyl includes but-1-ynyl, but-2-ynyl, but-3-ynyl, 1-methyl-prop-1-ynyl, 1-methyl-prop-2-ynyl, etc.

If a hydrocarbon chain carries both at least one double bond and also at least one triple bond, by definition it belongs to the alkynyl subgroup.

The above definition for alkynyl also applies if alkynyl is part of another group, as in C_(x-y)-alkynylamino or C_(x-y)-alkynyloxy, for example.

Unlike alkylene, alkynylene consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together by a C—C triple bond. If in an alkylene as hereinbefore defined having at least two carbon atoms, two hydrogen atoms in each case at adjacent carbon atoms are formally removed and the free valencies are saturated to form two further bonds, the corresponding alkynylene is formed.

Examples of alkynylene are ethynylene, propynylene, 1-methylethynylene, butynylene, 1-methylpropynylene, 1,1-dimethylethynylene, 1,2-dimethylethynylene, pentynylene, 1,1-dimethylpropynylene, 2,2-dimethylpropynylene, 1,2-dimethylpropynylene, 1,3-dimethylpropynylene, hexynylene etc.

By the generic terms propynylene, butynylene, pentynylene, hexynylene etc. without any further definition are meant all the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propynylene includes 1-methylethynylene and butynylene includes 1-methylpropynylene, 2-methylpropynylene, 1,1-dimethylethynylene and 1,2-dimethylethynylene.

The above definition for alkynylene also applies if alkynylene is part of another group, as in HO—C_(x-y)-alkynyleneamino or H₂N—C_(x-y)-alkynyleneoxy, for example.

By heteroatoms are meant oxygen, nitrogen and sulphur atoms.

Haloalkyl (haloalkenyl, haloalkenyl) is derived from the previously defined alkyl (alkenyl, alkynyl) by replacing one or more hydrogen atoms of the hydrocarbon chain independently of one another by halogen atoms, which may be identical or different. If a haloalkyl (haloalkenyl, haloalkynyl) is to be further substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogen-carrying carbon atoms.

Examples of haloalkyl (haloalkenyl, haloalkynyl) are —CF₃, —CHF₂, —CH₂F, —CF₂CF₃, —CHFCF₃, —CH₂CF₃, —CF₂CH₃, —CHFCH₃, —CF₂CF₂CF₃, —CF₂CH₂CH₃, —CF═CF₂, —CCl═CH₂, —CBr═CH₂, —Cl═CH₂, —C≡C—CF₃, —CHFCH₂CH₃, —CHFCH₂CF₃ etc.

From the previously defined haloalkyl (haloalkenyl, haloalkynyl) are also derived the terms haloalkylene (haloalkenylene, haloalkynylene). Haloalkylene (haloalkenyl, haloalkynyl), unlike haloalkyl, is bivalent and requires two binding partners. Formally, the second valency is formed by removing a hydrogen atom from a haloalkyl.

Corresponding groups are for example —CH₂F and —CHF—, —CHFCH₂F and —CHFCHF— or >CFCH₂F etc.

The above definitions also apply if the corresponding halogen groups are part of another group.

Halogen relates to fluorine, chlorine, bromine and/or iodine atoms.

Cycloalkyl is made up of the subgroups monocyclic hydrocarbon rings, bicyclic hydrocarbon rings and spiro-hydrocarbon rings. The systems are saturated. In bicyclic hydrocarbon rings two rings are joined together so that they have at least two carbon atoms together. In spiro-hydrocarbon rings a carbon atom (spiroatom) belongs to two rings together. If a cycloalkyl is to be substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogen-carrying carbon atoms. Cycloalkyl itself may be linked as a substituent to the molecule via every suitable position of the ring system.

Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[4.3.0]nonyl (octahydroindenyl), bicyclo[4.4.0]decyl (decahydronaphthalene), bicyclo[2.2.1]heptyl (norbornyl), bicyclo[4.1.0]heptyl (norcaranyl), bicyclo[3.1.1]heptyl (pinanyl), spiro[2.5]octyl, spiro[3.3]heptyl etc.

The above definition for cycloalkyl also applies if cycloalkyl is part of another group as in C_(x-y)-cycloalkylamino or C_(x-y)-cycloalkyloxy, for example.

If the free valency of a cycloalkyl is saturated, then an alicyclic group is obtained.

The term cycloalkylene can thus be derived from the previously defined cycloalkyl. Cycloalkylene, unlike cycloalkyl, is bivalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from a cycloalkyl.

Corresponding groups are for example

-   -   cyclohexyl and

The above definition for cycloalkylene also applies if cycloalkylene is part of another group as in HO—C_(x-y)-cycloalkyleneamino or H₂N—C_(x-y)-cycloalkyleneoxy, for example.

Cycloalkenyl is also made up of the subgroups monocyclic hydrocarbon rings, bicyclic hydrocarbon rings and spiro-hydrocarbon rings. However, the systems are unsaturated, i.e. there is at least one C—C double bond but no aromatic system. If in a cycloalkyl as hereinbefore defined two hydrogen atoms at adjacent cyclic carbon atoms are formally removed and the free valencies are saturated to form a second bond, the corresponding cycloalkenyl is obtained. If a cycloalkenyl is to be substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogen-carrying carbon atoms. Cycloalkenyl itself may be linked as a substituent to the molecule via every suitable position of the ring system.

Examples of cycloalkenyl are cycloprop-1-enyl, cycloprop-2-enyl, cyclobut-1-enyl, cyclobut-2-enyl, cyclopent-1-enyl, cyclopent-2-enyl, cyclopent-3-enyl, cyclohex-1-enyl, cyclohex-2-enyl, cyclohex-3-enyl, cyclohept-1-enyl, cyclohept-2-enyl, cyclohept-3-enyl, cyclohept-4-enyl, cyclobuta-1,3-dienyl, cyclopenta-1,4-dienyl, cyclopenta-1,3-dienyl, cyclopenta-2,4-dienyl, cyclohexa-1,3-dienyl, cyclohexa-1,5-dienyl, cyclohexa-2,4-dienyl, cyclohexa-1,4-dienyl, cyclohexa-2,5-dienyl, bicyclo[2.2.1]hepta-2,5-dienyl (norborna-2,5-dienyl), bicyclo[2.2.1]hept-2-enyl (norbornenyl), spiro[4.5]dec-2-ene etc.

The above definition for cycloalkenyl also applies when cycloalkenyl is part of another group as in C_(x-y)-cycloalkenylamino or C_(x-y)-cycloalkenyloxy, for example.

If the free valency of a cycloalkenyl is saturated, then an unsaturated alicyclic group is obtained.

The term cycloalkenylene can thus be derived from the previously defined cycloalkenyl.

Cycloalkenylene, unlike cycloalkenyl, is bivalent and requires two binding partners. Formally the second valency is obtained by removing a hydrogen atom from a cycloalkenyl. Corresponding groups are for example

cyclopentenyl and

etc.

The above definition for cycloalkenylene also applies when cycloalkenylene is part of another group as in HO—C_(x-y)-cycloalkenyleneamino or H₂N—C_(x-y)-cycloalkenyleneoxy, for example.

Aryl denotes a mono-, bi- or tricyclic group with at least one aromatic carbocycle. Preferably it denotes a monocyclic group with six carbon atoms (phenyl) or a bicyclic group with nine or ten carbon atoms (two six-membered rings or one six-membered ring with a five-membered ring), wherein the second ring may also be aromatic or, however, may also be saturated or partially saturated. If an aryl is to be substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogen-carrying carbon atoms. Aryl itself may be linked as a substituent to the molecule via every suitable position of the ring system.

Examples of aryl are phenyl, naphthyl, indanyl (2,3-dihydroindenyl), indenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl (1,2,3,4-tetrahydronaphthyl, tetralinyl), dihydronaphthyl (1,2-dihydronaphthyl), fluorenyl etc.

The above definition of aryl also applies when aryl is part of another group as in arylamino or aryloxy, for example.

If the free valency of an aryl is saturated, then an aromatic group is obtained.

The term arylene can also be derived from the previously defined aryl. Arylene, unlike aryl, is bivalent and requires two binding partners. Formally, the second valency is formed by removing a hydrogen atom from an aryl. Corresponding groups are e.g.

-   -   phenyl and

-   -   naphthyl and

etc.

The above definition for arylene also applies when arylene is part of another group as in HO-aryleneamino or H₂N-aryleneoxy for example.

Heterocyclyl denotes ring systems, which are derived from the previously defined cycloalkyl, cycloalkenyl and aryl by replacing one or more of the groups —CH₂— independently of one another in the hydrocarbon rings by the groups —O—, —S— or —NH— or by replacing one or more of the groups ═CH— by the group ═N—, wherein a total of not more than five heteroatoms may be present, at least one carbon atom may be present between two oxygen atoms and between two sulphur atoms or between one oxygen and to one sulphur atom and the ring as a whole must have chemical stability. Heteroatoms may optionally be present in all the possible oxidation stages (sulphur→sulphoxide —SO—, sulphone —SO₂—; nitrogen→N-oxide). In a heterocyclyl there is no heteroaromatic ring, i.e. no heteratom is part of an aromatic system.

A direct result of the derivation from cycloalkyl, cycloalkenyl and aryl is that heterocyclyl is made up of the subgroups monocyclic heterorings, bicyclic heterorings, tricyclic heterorings and spiro-heterorings, which may be present in saturated or unsaturated form. By unsaturated is meant that there is at least one double bond in the ring system in question, but no heteroaromatic system is formed. In bicyclic heterorings two rings are linked together so that they have at least two (hetero)atoms in common. In spiro-heterorings a carbon atom (spiroatom) belongs to two rings together. If a heterocyclyl is substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogen-carrying carbon and/or nitrogen atoms. Heterocyclyl itself may be linked as a substituent to the molecule via every suitable position of the ring system.

Examples of heterocyclyl are tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, thiazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, oxiranyl, aziridinyl, azetidinyl, 1,4-dioxanyl, azepanyl, diazepanyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidinyl, homopiperazinyl, homothiomorpholinyl, thiomorpholinyl-5-oxide, thiomorpholinyl-S,S-dioxide, 1,3-dioxolanyl, tetrahydropyranyl, tetrahydrothiopyranyl, [1,4]-oxazepanyl, tetrahydrothienyl, homothiomorpholinyl-S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridyl, dihydro-pyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienyl-5-oxide, tetrahydrothienyl-S,S-dioxide, homothiomorpholinyl-5-oxide, 2,3-dihydroazet, 2H-pyrrolyl, 4H-pyranyl, 1,4-dihydropyridinyl, 8-azabicyclo[3.2.1]octyl, 8-azabicyclo[5.1.0]octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 3,8-diaza-bicyclo[3.2.1]octyl, 2,5-diaza-bicyclo-[2.2.1]heptyl, 1-aza-bicyclo[2.2.2]octyl, 3,8-diaza-bicyclo[3.2.1]octyl, 3,9-diaza-bicyclo[4.2.1]nonyl, 2,6-diaza-bicyclo[3.2.2]nonyl, 1,4-dioxa-spiro[4.5]decyl, 1-oxa-3,8-diaza-spiro[4.5]decyl, 2,6-diaza-spiro[3.3]heptyl, 2,7-diaza-spiro[4.4]nonyl, 2,6-diaza-spiro[3.4]octyl, 3,9-diaza-spiro[5.5]undecyl, 2,8-diaza-spiro[4.5]decyl etc.

Further examples are the structures illustrated below, which may be attached via each hydrogen-carrying atom (exchanged for hydrogen):

The above definition of heterocyclyl also applies if heterocyclyl is part of another group as in heterocyclylamino or heterocyclyloxy for example.

If the free valency of a heterocyclyl is saturated, then a heterocyclic group is obtained.

The term heterocyclylene is also derived from the previously defined heterocyclyl. Heterocyclylene, unlike heterocyclyl, is bivalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from a heterocyclyl. Corresponding groups are for example

-   -   piperidinyl and

2,3-dihydro-1H-pyrrolyl and

etc.

The above definition of heterocyclylene also applies if heterocyclylene is part of another group as in HO-heterocyclyleneamino or H₂N-heterocyclyleneoxy for example.

Heteroaryl denotes monocyclic heteroaromatic rings or polycyclic rings with at least one heteroaromatic ring, which compared with the corresponding aryl or cycloalkyl (cycloalkenyl) contain, instead of one or more carbon atoms, one or more identical or different heteroatoms, selected independently of one another from among nitrogen, sulphur and oxygen, wherein the resulting group must be chemically stable. The prerequisite for the presence of heteroaryl is a heteroatom and a heteroaromatic system. If a heteroaryl is to be substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogen-carrying carbon and/or nitrogen atoms. Heteroaryl itself may be linked as a substituent to the molecule via every suitable position of the ring system, both carbon and nitrogen. Examples of heteroaryl are furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, pyridyl-N-oxide, pyrrolyl-N-oxide, pyrimidinyl-N-oxide, pyridazinyl-N-oxide, pyrazinyl-N-oxide, imidazolyl-N-oxide, isoxazolyl-N-oxide, oxazolyl-N-oxide, thiazolyl-N-oxide, oxadiazolyl-N-oxide, thiadiazolyl-N-oxide, triazolyl-N-oxide, tetrazolyl-N-oxide, indolyl, isoindolyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, benzotriazinyl, indolizinyl, oxazolopyridyl, imidazopyridyl, naphthyridinyl, benzoxazolyl, pyridopyridyl, purinyl, pteridinyl, benzothiazolyl, imidazopyridyl, imidazothiazolyl, quinolinyl-N-oxide, indolyl-N-oxide, isoquinolyl-N-oxide, quinazolinyl-N-oxide, quinoxalinyl-N-oxide, phthalazinyl-N-oxide, indolizinyl-N-oxide, indazolyl-N-oxide, benzothiazolyl-N-oxide, benzimidazolyl-N-oxide etc.

Further examples are the structures illustrated below, which may be attached via each hydrogen-carrying atom (exchanged for hydrogen):

The above definition of heteroaryl also applies when heteroaryl is part of another group as in heteroarylamino or heteroaryloxy, for example.

If the free valency of a heteroaryl is saturated, a heteroaromatic croup is obtained.

The term heteroarylene can therefore be derived from the previously defined heteroaryl. Heteroarylene, unlike heteroaryl, is bivalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from a heteroaryl. Corresponding groups are for example

-   -   pyrrolyl and etc.

The above definition of heteroarylene also applies when heteroarylene is part of another group as in HO-heteroaryleneamino or H₂N-heteroaryleneoxy, for example.

The above-mentioned bivalent groups (alkylene, alkenylene, alkynylene etc.) may also be a part of composite groups (e.g. H₂N—C₁₋₄alkylene or HO—C₁₋₄alkylene-). In this case one of the valencies is saturated by the attached group (in this case: —NH₂, —OH), so that a composite group of this kind in this nomenclature amounts in total to only a monovalent substituent.

By substituted is meant that a hydrogen atom which is bound directly to the atom under consideration, is replaced by another atom or another group of atoms (substituent). Depending on the starting conditions (number of hydrogen atoms) mono- or polysubstitution may take place on one atom. Substitution with a particular substituent is only possible if the permitted valencies of the substituent and of the atom that is to be substituted correspond to one another and the substitution leads to a stable compound (i.e. to a compound which is not converted spontaneously, e.g. by rearrangement, cyclisation or elimination).

Bivalent substituents such as ═S, ═NR, ═NOR, ═NNRR, ═NN(R)C(O)NRR, ═N₂ or the like, may only be substituents at carbon atoms, wherein the bivalent substituent ═O may also be a substituent at sulphur. Generally, substitution may be carried out by a bivalent substituent only at ring systems and requires replacement by two geminal hydrogen atoms, i.e. hydrogen atoms that are bound to the same carbon atom that is saturated prior to the substitution. Substitution by a bivalent substituent is therefore only possible at the group —CH²⁻ or sulphur atoms of a ring system.

Stereochemistry/Solvates/Hydrates:

Unless stated otherwise a structural formula given in the description or in the claims or a chemical name refers to the corresponding compound itself, but also encompasses the tautomers, stereoisomers, optical and geometric isomers (e.g. enantiomers, diastereomers, E/Z isomers, etc.), racemates, mixtures of separate enantiomers in any desired combinations, mixtures of diastereomers, mixtures of the forms mentioned hereinbefore (if such forms exist) as well as salts, particularly pharmaceutically acceptable salts thereof. The compounds and salts according to the invention may be present in solvated form (e.g. with pharmaceutically acceptable solvents such as e.g. water, ethanol etc.) or in unsolvated form. Generally, for the purposes of the present invention the solvated forms, e.g. hydrates, are to be regarded as of equal value to the unsolvated forms.

Salts:

The term “pharmaceutically acceptable” is used herein to denote compounds, materials, compositions and/or formulations which are suitable, according to generally recognised medical opinion, for use in conjunction with human and/or animal tissue and do not have or give rise to any excessive toxicity, irritation or immune response or lead to other problems or complications, i.e. correspond overall to an acceptable risk/benefit ratio.

The term “pharmaceutically acceptable salts” relates to derivatives of the chemical compounds disclosed in which the parent compound is modified by the addition of acid or base. Examples of pharmaceutically acceptable salts include (without being restricted thereto) salts of mineral or organic acids in relation to basic functional groups such as for example amines, alkali metal or organic salts of acid functional groups such as for example carboxylic acids, etc. These salts include in particular acetate, ascorbate, benzenesulphonate, benzoate, besylate, bicarbonate, bitartrate, bromide/hydrobromide, Ca-edetate/edetate, camsylate, carbonate, chloride/hydrochloride, citrate, edisylate, ethane disulphonate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, glycollylarsnilate, hexylresorcinate, hydrabamine, hydroxymaleate, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, malate, maleate, mandelate, methanesulphonate, mesylate, methylbromide, methylnitrate, methylsulphate, mucate, napsylate, nitrate, oxalate, pamoate, pantothenate, phenyl acetate, phosphate/diphosphate, polygalacturonate, propionate, salicylate, stearate, subacetate, succinate, sulphamide, sulphate, tannate, tartrate, teoclate, toluenesulphonate, triethiodide, ammonium, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumin and procaine. Other pharmaceutically acceptable salts may be formed with cations of metals such as aluminium, calcium, lithium, magnesium, potassium, sodium, zinc, etc. (cf. also Pharmaceutical salts, Birge, S. M. et al., J. Pharm. Sci., (1977), 66, 1-19).

The pharmaceutically acceptable salts of the present invention may be prepared starting from the parent compound which carries a basic or acidic functionality, by conventional chemical methods. Generally, such salts may be synthesised by reacting the free acid or base form of these compounds with a sufficient amount of the corresponding base or acid in water or an organic solvent such as for example ether, ethyl acetate, ethanol, isopropanol, acetonitrile (or mixtures thereof).

Salts of acids other than those mentioned above, which are useful for example for purifying or isolating the compounds from the reaction mixtures (e.g. trifluoroacetates), are also to be regarded as part of the invention.

In a representation such as for example

the letter A has the function of a ring designation in order to make it easier, for example, to indicate the attachment of the ring in question to other rings.

For bivalent groups in which it is crucial to determine which adjacent groups they bind and with which valency, the corresponding binding partners are indicated in brackets, where necessary for clarification purposes, as in the following representations:

or (R²)—C(O)NH— or (R²)—NHC(O)—;

Groups or substituents are frequently selected from among a number of alternative groups/substituents with a corresponding group designation (e.g. R^(a), R^(b) etc). If such a group is used repeatedly to define a compound according to the invention in different molecular parts, it must always be borne in mind that the various uses are to be regarded as totally independent of one another.

By a therapeutically effective amount for the purposes of this invention is meant a quantity of substance that is capable of obviating symptoms of illness or of preventing or alleviating these symptoms, or which prolong the survival of a treated patient.

LIST OF ABBREVIATIONS

aa amino acid Ac acetyl equiv. equivalent(s) Ar (hetero)aryl ATP adenosine triphosphate Boc tert-butyloxycarbonyl BSA bovine serum albumin Bu butyl d day(s) TLC thin layer chromatography DCC dicyclohexylcarbodiimide DCM dichloromethane DEA diethylamine DIC diisopropylcarbodiimide DIPEA N-ethyl-N,N-diisopropylamine (HÜNIG-base) DMA N,N-dimethylacetamide DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide DMF-DMA N,N-dimethylformamide-dimethylacetal DMSO dimethylsulphoxide dppf 1,1′-bis(diphenylphosphino)ferrocene EDC N-(3-dimethylaminopropyl)-N4-ethylcarbodiimide hydrochloride ESI electron spray ionization Et ethyl EtOH ethanol h hour(s) HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl- uronium hexafluorophosphate HCl hydrochloric acid het hetero HPLC high performance liquid chromatography HÜNIG base N-ethyl-N,N-diisopropylamine i iso iPr₂NEt diisopropylethylamine (HÜNIG base) iPrOH isopropanol cat. catalyst, catalytic conc. concentrated LC liquid chromatography sin. solution M molar Me methyl MeOH methanol min minute(s) mL milliliters MPLC medium pressure liquid chromatography MS mass spectrometry MW microwave N normal NMP N-methylpyrrolidinone PBS phosphate-buffered saline Pd-dppf 1,1′-bis(diphenylphosphino)ferrocene palladium(II)- dichloride dichloromethane Ph phenyl PK pharmacokinetics Pr propyl R_(f) (Rf) retention factor RP reversed phase RT ambient temperature s second(s) TBTU O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium tetrafluoroborate TEA triethylamine tert tertiary Tf triflate TFA trifluoroacetic acid THF tetrahydrofuran TMS trimethylsilyl Tos tosyl t_(Ret.) retention time (HPLC) TRIS tris(hydroxymethyl)-aminomethane UV ultraviolet

Features and advantages of the present invention will become apparent from the following detailed Examples, which illustrate the fundamentals of the invention by way of example, without restricting its scope:

Preparation of the Compounds According to the Invention

General

Unless stated otherwise, all the reactions are carried out in commercially obtainable apparatus using methods that are commonly used in chemical laboratories. Starting materials that are sensitive to air and/or moisture are stored under protective gas and corresponding reactions and manipulations therewith are carried out under protective gas (nitrogen or argon).

The compounds are named according to the Beilstein rules using the Autonom software (Beilstein). If a compound is to be represented both by a structural formula and by its nomenclature, in the event of a conflict the structural formula is decisive.

Microwave reactions are carried out in an initiator/reactor made by Biotage or Synthos 3000 and Monowave 300 made by the company Anton Paar in sealed containers (preferably 2, 5 or 20 mL), preferably with stirring.

Chromatography

Thin layer chromatography is carried out on ready-made TLC plates of silica gel 60 on glass (with fluorescence indicator F-254) made by Merck.

The preparative high pressure chromatography (HPLC) of the example compounds according to the invention is carried out with columns made by Waters (names: Sunfire C18, 5 μm, 30×100 mm Part. No. 186002572; X-Bridge C18, 5 μm, 30×100 mm Part. No. 186002982).

The compounds are eluted using either different gradients of H₂O/acetonitrile or H₂O/MeOH, wherein preferably 0.1% HCOOH is added to the water (acid conditions). For chromatography under basic conditions H₂O/acetonitrile gradients are also used, and the water is made basic according to the following recipe: 5 mL of an ammonium hydrogen carbonate solution (158 g to 1 L H₂O) and 2 mL ammonia (7M in MeOH) are made up to 1 L with H₂O.

The normal-phase preparative high pressure chromatography (HPLC) of the example compounds according to the invention is carried out with columns made by Macherey & Nagel (name: Nucleosil, 50-7, 40×250 mm) and VDSoptilab (name: Kromasil 100 NH₂, 10 μM, 50×250 mm). The compounds are eluted using different gradients of DCM/MeOH, with 0.1% NH₃ added to the MeOH.

The analytical HPLC (reaction monitoring) of intermediate compounds is carried out with columns made by Agilent, Waters and Phenomenex. The analytical equipment is also provided with a mass detector in each case.

HPLC Mass Spectroscopy/UV Spectrometry

The retention times/MS-ESL for characterising the example compounds according to the invention are produced using an HPLC-MS apparatus (high performance liquid chromatography with mass detector) made by Agilent. Compounds that elute at the injection peak are given the retention time t_(Ret.)=0.00.

HPLC-Methods

Preparative

prep. HPLC1 HPLC: 333 and 334 Pumps Column: Waters X-Bridge C18, 5 μm, 30 × 100 mm, Part. No. 186002982 Eluant: A: 10 mM NH₄HCO₃ in H₂O; B: acetonitrile (HPLC grade) Detection: UV/Vis-155 Flow: 50 mL/min Gradient: 0.00 min: 5% B 3.00-15.00 min: variable (see individual methods) 15.00-17.00 min: 100% B prep. HPLC2 HPLC: 333 and 334 Pumps Column: Waters Sunfire C18, 5 μm, 30 × 100 mm, Part. No. 186002572 Eluant: A: H₂O + 0.2% HCOOH; B: acetonitrile (HPLC grade) + 0.2% HCOOH Detection: UV/Vis-155 Flow: 50 mL/min Gradient: 0.00 min: 5% B 3.00-15.00 min: variable (see individual methods) 15.00-17.00 min: 100% B Analytical Method A

HPLC Agilent 1100 Series MS 1100 Series LC/MSD SL (MM-ES + APCI, +3000 V, Quadrupol, G1956B) MSD signal settings Scan pos 120-750 column Waters, XBridge, C18, 3.5 μm, 135 Å, 30 × 2.1 mm column, Part. No: 186003020 eluant A: 5 mM NH₄HCO₃/20 mM NH₃ (pH = 9.5) B: acetonitrile (HPLC grade) detection signal UV 254/214 nm (bandwidth 8, reference off) spectrum range: 190-400 nm; step: 2.0 nm peak width >00025 min (0.05 s) injection 2 μL standard injection flow 1.0 mL/min column temperature 35° C. gradient 0.0-1.0 min 15% → 95% B 1.0-1.6 min 95% B 1.6-1.7 min 95% → 15% B 1.7-2.3 min 15% B Method B

HPLC Agilent 1100 Series MS 1100 Series LC/MSD SL (MM-ES + APCI, +3000 V, Quadrupol, G1956B) MSD signal settings Scan pos 120-750 column Waters, XBridge, C18, 3.5 μm, 135 Å, 30 × 2.1 mm column, Part. No.: 186003020 eluant A: 5 mM NH₄HCO₃/20 mM NH₃ (pH = 9.5) B: MeOH (HPLC grade) detection signal UV 254/214 nm (bandwidth 8, reference off) spectrum range: 190-400 nm; step: 2.0 nm peak width >00025 min (0.05 s) injection 2 μL standard injection flow 1.0 mL/min column temperature 40° C. gradient 0.0-1.0 min 20% → 95% B 1.0-2.0 min 95% B 2.0-2.1 min 95% → 20% B 2.1-2.3 min 20% B Method C

HPLC Agilent 1100 Series MS 1200 Series LC/MSD (API-ES + 3000 V, Quadrupol, G6140A) MSD signal settings Scan pos 150-750 column Agilent. Zorbax SB, C8, 3.5 μm, 80 Å, 50 × 2.1 mm column, Part. No.: 871700-906 eluant A: water + 0.11% formic acid B: acetonitrile (HPLC grade) + 0.1% formic acid detection signal UV 254/214/230 nm (bandwidth 8, reference off) spectrum range: 190-450 nm; step: 4.0 nm peak width >0.01 min (0.2 s) injection 1.5 μL standard injection flow 1.1 mL/min column temperature 45° C. gradient 0.0-1.75 min 15% → 95% B 1.75-1.9 min 95% B 1.9-1.92 min 95% → 15% B 1.92-2.1 min 15% B Method D

HPLC Agilent 1100 Series MS 1100 Series LC/MSD SL (MM-ES + APCI, +2500 V, Quadrupol, G1956B) MSD signal settings Scan pos 70-500 column Agilent Zorbax SB, C8, 3.5 μm, 80 Å, 50 × 2.1 mm column, Part. No.: 871700-906 eluant A: water + 0.11% formic acid B: MeOH (HPLC grade) detection signal UV 254/214/230 nm (bandwidth 8, reference off) spectrum range: 190-450 nm; step: 4.0 nm peak width >0.01 min (0.2 s) injection 1.5 μL standard injection flow 1.0 mL/min column temperature 45° C. gradient 0.0-1.5 min 20% → 95% B 1.5-2.1 min 95% B 2.1-2.2 min 95% → 20% B 2.2-2.4 min 20% B Method E

HPLC Agilent 1100 Series MS 1100 Series LC/MSD SL (MM-ES + APCI, +3000 V, Quadrupol, G1956B) MSD signal settings Scan pos 100-750 column Waters, XBridge, C18, 3.5 μm, 135 Å, 30 × 2.1 mm column, Part. No.: 186003020 eluant A: 5 mM NH₄HCO₃/20 mM NH₃ (pH = 9.5) B: acetonitrile (HPLC grade) detection signal UV 254/214 nm (bandwidth 8, reference off) spectrum range: 190-400 nm; step: 2.0 nm peak width >0005 min (0.1 s) injection 2 μL standard injection flow 1.0 mL/min column temperature 35° C. gradient 0.0-1.0 min 15% → 95% B 1.0-1.6 min 95% B 1.6-1.7 min 95% → 15% B 1.7-2.3 min 15% B Method F

HPLC Agilent 1100 Series MS 1200 Series LC/MSD (API-ES + 2500 V, Quadrupol, G6140A) MSD signal settings Scan pos 75-500 column Agilent Zorbax SB, C8, 3.5 μm, 80 Å, 50 × 2.1 mm column, Part. No.: 871700-906 eluant A: water + 0.11% formic acid B: acetonitrile (HPLC grade) + 0.1% formic acid detection signal UV 254/214/230 nm (bandwidth 8, reference off) spectrum range: 190-450 nm; step: 4.0 nm peak width >0.01 min (0.2 s) injection 1.5 μL standard injection flow 1.1 mL/min column temperature 45° C. gradient 0.0-1.75 min 15% → 95% B 1.75-1.9 min 95% B 1.9-1.92 min 95% → 15% B 1.92-2.1 min 15% B Method G

HPLC Agilent 1100 Series MS 1100 Series LC/MSD (API-ES +/− 3000 V, Quadrupol, G1946D) MSD signal settings Scan pos 120-900, Scan neg 120-900 column phenomenex; Part. No. 00M-4439-BO-CE; Gemini 3 μm, C18, 110 Å; 20 × 2.0 mm column eluant A: 5 mM NH₄HCO₃/20 mM NH₃ (pH = 9.5) B: acetonitrile (HPLC grade) detection signal UV 254 nm (bandwidth 1, reference off) spectrum range: 250-400 nm; step: 1 nm peak width <0.01 min (0.1 s) injection 10 μL standard injection flow 1.0 mL/min column temperature 40° C. gradient 0.0-2.5 min  5% → 95% B 2.5-2.8 min 95% B 2.8-3.1 min 95% → 5% B Method H

HPLC Agilent G1312A binary pump with Waters 2996 PDA detector MS Waters ZQ MSD Signal Settings Scan pos 150-850 column Waters; Part. No. 186001295; Atlantis dC18, 2.1 × 100.0 mm, 3 μm column eluant A: 0.1% formic acid in water B: 0.1% formic acid in acetonitrile (HPLC grade) detection signal UV 215 nm spectrum range: 200-420 nm; step: 1 nm injection 3 μL flow 0.6 mL/min column temperature 40° C. gradient     0.0 min  5% B  0.0-5.0 min  5% → 100% B  5.0-5.4 min 100% B 5.4-5.42 min 100% → 5% B 5.42-7.0 min  5% B Method I

HPLC Shimadzu Prominence Series MS Shimadzu LCMS-2010EV system MSD Signal Settings Scan pos 100-1000 column Waters; Part. No. 186001291; Atlantis dC18, 2.1 × 50.0 mm, 3 μm column eluant A: 0.1% formic acid in water B: 0.1% formic acid in acetonitrile (HPLC grade) detection signal UV 215 nm spectrum range: 210-420 nm; step: 1 nm injection 3 μL flow 1.0 mL/min column temperature 40° C. gradient     0.0 min  5% B  0.0-2.5 min  5% → 100% B  2.5-2.7 min 100% B  2.7-2.71 min 100% → 5% B 2.71-3.50 min  5% B

Method J

HPLC Agilent G1312A binary pump with Waters 2996 PDA detector MS Waters LCT (MS5) or Waters ZQ (MS10) MSD Signal Settings Scan pos 150-850 column Phenomenex; Part No. 00D-4453-B0; Gemini C18, 2.0 × 100.0 mm, 3 μm column eluant A: 2 mM NH₄HCO₃ buffered to pH = 10 B: acetonitrile (HPLC grade) detection signal UV 215 nm spectrum range: 200-420 nm; step: 1 nm injection 3 μL flow 0.5 mL/min column temperature 50° C. gradient     0.0 min   5% B  0.0-5.5 min  5% → 100% B  5.5-5.9 min 100% B 5.9-5.92 min 100% → 5% B 5.92-9.0 min   5% B Method K

HPLC Shimadzu Prominence Series MS Shimadzu LCMS-2010EV System MSD Signal Settings Scan pos 100-1000 column Waters; Part. No. 186001287; Atlantis dC18, 2.1 × 30.0 mm, 3 μm column eluant A: 0.1% formic acid in water B: 0.1% formic acid in acetonitrile (HPLC grade) detection signal UV 215 nm spectrum range: 220-420 nm; step: 1 nm injection 3 μL flow 1.0 mL/min column temperature 40° C. gradient     0.0 min   5% B  0.0-1.5 min  5% → 100% B  1.5-1.6 min 100% B 1.6-1.61 min 100% → 5% B Method L

HPLC Agilent 1100 Series MS 1100 Series LC/MSD SL (MM-ES + APCI, +3000 V, Quadrupol, G1956B) MSD Signal Settings Scan pos 120-750 column Waters, XBridge, C18, 5.0 pm, 50 × 2.1 mm column, Part. No.: 186003108 eluant A: 5 mM NH₄HCO₃/20 mM NH₃ (pH = 9.5) B: acetonitrile (HPLC grade) detection signal UV 254/214 nm (bandwidth 8, reference off) spectrum range: 190-400 nm; step: 2.0 nm peak width >00025 min (0.05 s) injection 2 μL standard injection flow 1.2 mL/min column temperature 35° C. gradient 0.0-1.25 min  5% → 100% B 1.25-2.0 min 100% B  2.0-3.1 min 100% → 5% B Method M

HPLC Agilent 1100 Series MS Agilent LC/MSD SL MSD Signal Settings MS: Positive and negative Mass range: 120-900 m/z column Waters, Xbridge C18 ™, 2.5 μm, 2.1 × 20 mm, Part. No.186003201 eluant A: 20 mM NH₄HCO₃/NH₃ pH 9 B: acetonitrile (HPLC grade) detection signal UV, bandwidth 170 nm, reference off spectrum range: 230-400 nm; step: 1.0 nm peak width <0.01 min injection 5 μL standard injection flow 1.0 mL/min column temperature 60° C. gradient   0.0 min 10% B 0.0-1.5 min 10% → 95% B 1.5-2.0 min 95% B 2.0-2.1 min 95% → 10% B Method N

HPLC Agilent 1100 Series MS 1200 Series LC/MSD (API-ES +/− 3000 V, Quadrupol, G6130A) MSD Signal Settings Scan pos 105-1200, Scan neg. 105-1200 column Waters, XBridge, C18, 5 μm, 135 Å, 30 × 2.1 mm column, Part. No.: 186003108 eluant A: 5 mM NH₄HCO₃/19 mM NH₃ (pH = 9.5) B: acetonitrile (HPLC grade) detection signal UV 254/230 nm (bandwidth 8, reference off) spectrum range: 190-450 nm; step: 4.0 nm peak width >0.03 min (0.5 s) injection 2 μL standard injection flow 1.2 mL/min column temperature 35° C. gradient 0.0-1.25 min  5% → 95% B 1.25-2.0 min 95% B 2.0-2.01 min 95% → 5% B 2.01-3.0 min  5% B

Method O

HPLC Agilent 1200 Series MS 1100 Series LC/MSD (API-ES +/− 3000 V, Quadrupol, G1946D) MSD Signal Settings Scan pos 105-1200, Scan neg. 105-1200 column Waters, XBridge, C18, 5 μm, 135 Å, 30 × 2.1 mm column, Part. No.: 186003108 eluant A: 5 mM NH₄HCO₃/19 mM NH₃ (pH = 9.5) B: acetonitrile (HPLC grade) detection signal UV 254/230 nm (bandwidth 8, reference off) spectrum range: 190-450 nm; step: 4.0 nm peak width >0.03 min (0.5 s) injection 2 μL standard injection flow 1.2 mL/min column temperature 35° C. gradient 0.0-1.25 min  5% → 100% B 1.25-2.0 min 100% B 2.0-2.01 min 100% → 5% B 2.01-3.0 min  5% B Method P

HPLC Agilent 1100 Series MS Agilent LC/MSD SL MSD Signal Settings MS: Positive and negative Mass range: 120-800 m/z column Waters, XBridge ™ C18, 2.5 μm, 2.1 × 20 mm; Part. No. 186003201 eluant A: 0.1% NH₃ (pH = 9-10) B: acetonitrile (HPLC grade) detection signal UV, bandwidth 170 nm, reference off spectrum range: 230-400 nm; step: 2.0 nm peak width <0.01 min injection 5 μL standard injection flow 1.0 mL/min column temperature 60° C. gradient 0.0  5% B  0.0-2.5 min  5% → 95% B  2.5-2.8 min 95% B 2.81-3.1 min  5% → 95% B Method Q

HPLC Agilent 1100 column AD-H (Messrs. Chiralcel; 4.6 × 150 mm) eluant MeOH + 0.1% DEA flow 0.7 mL/min column temperature 40° C. gradient isocratic Method R

HPLC Agilent 1100 column LUX2 (Messrs. Phenomenex; 4.6 × 150 mm) eluant MeOH + 0.1% DEA flow 0.7 mL/min column temperature 40° C. gradient isocratic

The compounds according to the invention are prepared by the methods of synthesis described hereinafter, in which the substituents of the general formulae have the meanings given hereinbefore. These methods are intended as an illustration of the invention, without restricting its subject matter and the scope of the compounds claimed to these examples. Where the preparation of starting compounds is not described, they are commercially obtainable or may be prepared analogously to known compounds or methods described herein. Substances described in the literature are prepared according to the published methods of synthesis.

General Formula Scheme and Summary of the Synthesis Route

In principle, 2,4-diaminopyrimidine derivatives may be prepared from correspondingly substituted chloropyrimidines. The reactivity of these chloropyrimidines is controlled by the substituent in position 5, with the result that different synthesis strategies have to be adopted depending on the nature of this substituent.

For all the substituents with the exception of the trifluoromethyl group (—CF₃) functionalisation may be carried out in the 4 position as the first step. By reacting the 2,4-dichloro compound A1 with the corresponding amine R⁴—NH₂ the intermediate B is obtained, which may in turn be converted into the 2,4-diaminopyrimidine C1 by reaction with a (hetero)aromatic amine R²—NH₂.

Alternatively, 2,4-diaminopyrimidines C1 may also be prepared starting from 2-methylsulphanyl-3H-pyrimidin-4-one by reacting with a (hetero)aromatic amine R²—NH₂ followed by halogenation in position 5 via the intermediates D and E. The cyclic amide E may be reacted with phosphoryl chloride to obtain the 4-chloropyrimidine F1, which in turn leads to C1 by reaction with a correspondingly configured amine R⁴—NH₂.

2,4-Dichloropyrimidine A2 substituted in position 5 by a trifluoromethyl group may be reacted in the presence of zinc chloride with a (hetero)aromatic amine R²—NH₂ and thus yields the 4-chloropyrimidine F2, which may in turn be reacted with amines R⁴—NH₂ and converted into the 2,4-diaminopyrimidine C2.

The 2,4-diaminopyrimidines C1 and C2 may on the one hand be end compounds (I) according to the invention or on the other hand may be prepared using correspondingly protected amines in positions 2 and 4, deprotected by conventional methods and then converted into the actual end compounds (I) designated G1 or G2 by one or more derivatisation steps such as e.g. amide formation, alkylation or amination reactions. Instead of protected amines it is also possible to use synthesis components which can be directly functionalised or derivatised without recourse to protective groups.

In end compounds (I) according to the invention the group R² corresponds to a grouping having the structure

and the group R⁴ to a grouping having the structure

1. Preparation of the Oxindole Components (=amine R⁴—NH₂)

1.1 Preparation of 4-cyanooxindole (Method A)

4-bromoxindole (2.0 g, 9.43 mmol), zinc cyanide (680 mg, 5.68 mmol), tris(bisbenzylideneacetone)dipalladium (250 mg, 0.27 mmol) and 1,1′-diphenylphosphineferrocene (300 mg, 0.54 mmol) are stirred in anhydrous DMF (10 mL) for 2 h at 140° C. under argon. The reaction mixture is cooled and poured onto 30% aqueous ethanol. The precipitate is filtered off, digested with water and EtOH and dried.

1.2 Preparation of 4-cyano-3,3-dimethyloxindole (Method B)

4-cyanooxindole (6.80 g, 43.0 mmol) in anhydrous THF (40 mL) is combined with sodium hydride (60% dispersion in white oil, 7.0 g, 175 mmol) at −72° C. under argon and stirred for 20 min at this temperature. Methyl iodide (4.0 mL, 64.3 mmol) is added, the reaction mixture is slowly heated to RT and stirred for 48 h. The mixture is combined at −72° C. with saturated ammonium chloride solution (38 mL) and divided between water and EtOAc. The aqueous phase is exhaustively extracted with EtOAc, the combined organic phases are washed with water and saturated saline solution, dried on sodium sulphate, filtered and evaporated down. The crude product is crystallised or purified by column chromatography.

Additional alkylation at the nitrogen is obtained using 6 equiv. NaH and 7 equiv. methyl iodide. Moreover, an alkylating agent other than methyl iodide may be used.

1.3 Preparation of 4-cyano-3-spirocyclopropyloxindole (Method C)

4-cyanooxindole (500 mg, 3.16 mmol) are taken up in 2 mL anhydrous DMF and combined with 248 μL (2.85 mmol) 1,2-dibromoethane. After the solution has been cooled to 0° C., 379 mg NaH (9.5 mmol, 60% dispersion in oil) are added and the reaction mixture is stirred for 16 h at RT. It is mixed with several millilitres of saturated aqueous ammonium chloride solution, extracted 3× with EtOAc and the combined organic phases are dried on sodium sulphate. After elimination of the volatile constituents in vacuo the residue is purified by chromatography (RP phase).

TABLE 1 t_(ret) method of intermediate [min] [M + H]⁺ analysis

0.44 — C

0.72 187.2 C

0.84 201.2 C

0.75 215.2 C

1.03 243.2 C

1.15 189 L 1.4 Preparation of 4-aminomethyl-3,3-dimethyloxindole (Method D)

4-cyano-3,3-dimethyloxindole (3.70 g, 19.9 mmol) in MeOH (35 mL) and 6 N HCl (15 mL) is mixed with platinum oxide (500 mg) and hydrogenated for 17 h at RT under a hydrogen pressure of 5 bar. The reaction mixture is filtered and evaporated down.

4-cyano-3-spirocyclopropyloxindole is hydrogenated using Raney nickel and methanolic ammonia as solvent (method E).

Further 4-cyanooxindoles may also be hydrogenated analogously.

TABLE 2 t_(ret) method of intermediate [min] [M + H]⁺ analysis

0.13 163.2 C

0.13 191.0 C

0.18 205.2 C

0.16 219.2 C

0.37 247.2 C

1.07 185 G 2. Preparation of the Intermediates/Example Compounds C1 and G1 or (I) 2.1 Variant 1

2.1.1 Synthesis of intermediate B-1 (Method F).

2,4,5-trichloropyrimidine A1-1 (0.30 mL, 2.61 mmol) in anhydrous DCM is combined at 0° C. with N-ethyldiisopropylamine (1.4 mL, 8.0 mmol) and 4-aminomethyl-3,3-dimethyloxindole (653 mg, 2.88 mmol) and stirred for 30 min at RT. The reaction mixture is washed with dil. ammonium chloride solution and water, the organic phase is dried on sodium sulphate, filtered, evaporated down and crystallised with water.

The bromine analogue B-2 is prepared analogously starting from 5-bromo-2,4-dichloropyrimidine.

TABLE 3 t_(ret) method of intermediate Structure [min] [M + H]⁺ analysis B-1

0.84 337.0 C B-2

2.1.2 General Synthesis of Intermediates/Example Compounds C1 or (I) Starting from Intermediates B (Method G).

A mixture of the corresponding 2-chloropyrimidine B (0.22 mmol), the (hetero)aromatic amine R²—NH₂ (0.29 mmol) and methanesulphonic acid (0.77 mmol) is stirred for 18 h in anhydrous 2-propanol (400 μL) at 90° C. The reaction mixture is purified by preparative HPLC-MS. The fractions containing the reaction product are freeze-dried.

Instead of methanesulphonic acid p-toluenesulphonic acid or trifluoroacetic acid may be used. Instead of 2-propanol, 4-methyl-2-pentanol may be used as solvent. If the amine used, R²—NH₂, has a BOC protective group this is cleaved in situ under the acidic reaction conditions.

The following intermediates/example compounds C1 or (I) are prepared by this method (Table 4):

TABLE 4 Intermediate t_(ret) method of (Example) Structure [min] [M + H]⁺ analysis C1-1 (I-1)

0.68 550.2 C C1-2 (I-2)

1.47 509.3 G C1-3¹ (I-3)

2.30 699   K C1-4¹ (I-4)

2.20 743   I C1-5² (I-5)

1.40 535   G C1-6² (I-6)

1.60 491   L C1-7^(2,3) (I-7)

1.91 535.2/537.3 G C1-9^(2,3) (I-238)

1.33 521/523 P C1-10² (I-239)

1.56 535/537 O C1-11² (I-240)

1.59 552/554 O C1-12^(2,3) (I-241)

1.53 551/553 O C1-13² (I-242)

1.75 551/553 O C1-14² (I-243)

1.61 535/537 O C1-15² (I-244)

1.47 549/551 P C1-16^(2,3) (I-245)

1.65 549/551 N C1-17^(2,3) (I-246)

1.62 507/509 O C1-18^(2,3) (I-247)

1.59 491/493 O C1-19² (I-248)

1.75 508/510 O C1-20² (I-249)

1.21 492/494 P C1-21² (I-250)

1.04 491/493 P C1-22² (I-251)

1.43 505/507 P C1-23^(2,3) (I-252)

1.60 477/479 N C1-24^(2,3) (I-253)

1.63 505/507 N C1-25² (I-254)

1.68 508/510 P C1-26² (I-255)

1.68 509/511 N C1-27² (I-256)

1.66 505/507 N C1-28² (I-257)

1.65 506/508 O C1-29² (I-258)

1.75 561/563 N C1-30² (I-259)

1.51 522/524 O C1-31² (I-260)

1.71 543/545 N ¹cf. WO 2002/030927 ²synthesis using a BOC-protected amine R²—NH₂ and cleaving in situ ³racemic representation of the structural formula explicitly includes both configurations in each case, i.e.

2.2 Variant 2

2.2.1 Synthesis of Intermediate D-1 (Method H).

2-methylsulphanyl-3H-pyrimidin-4-one (1.50 g, 10.55 mmol) and 4-(4-methylpiperazinyl)aniline (1.82 g, 9.50 mmol) in anhydrous NMP (5 mL) are stirred for 40 min at 210° C. in a microwave reactor. The reaction mixture is lyophilised and the residue is purified by chromatography.

TABLE 5 method t_(ret) [M + of Intermediate structure [min] H]⁺ analysis D-1

0.49 286.2 B 2.2.2 Synthesis of intermediate E-1 (method

D-1 (910 mg, 3.19 mmol) in anhydrous acetic acid (5 mL) is combined at 0° C. with bromine (180 μL, 3.51 mmol) in anhydrous acetic acid (5 mL) and stirred for 60 min at RT. The precipitated solid is isolated by filtration.

TABLE 6 method Inter- t_(ret) of mediate structure [min] [M + H]⁺ analysis E-1

0.51 364/366 B 2.2.3 Synthesis of intermediate F1-1 (method I).

E-1 (780 mg, 2.14 mmol) in phosphorus oxychloride (8 mL) is stirred for 30 min at boiling temperature. The mixture is cooled to 0° C., dropped onto ice, neutralised with saturated potassium carbonate solution and exhaustively extracted with DCM. The organic phase is washed with water, dried on sodium sulphate, filtered and evaporated down.

TABLE 7 method Inter- t_(ret) of mediate structure [min] [M + H]⁺ analysis F1-1

1.05 382/384 B 2.2.4 Synthesis of Example compound I-8 (C1-8) (Method I).

A mixture of F1-1 (70 mg, 0.18 mmol), N-ethyldiisopropylamine (0.64 mmol) and 4-aminomethyl-1,3-dihydro-indol-2-one (38 mg, 0.19 mmol) is stirred in anhydrous NMP (400 μL) for 10 min at 120° C. in a microwave reactor (Synthos 3000 made by Anton Paar, Rotor 4×24 MG5). The reaction mixture is purified by preparative HPLC-MS. The fractions containing the reaction product are freeze-dried.

TABLE 8 Ex- t_(ret) method of ample Structure [min] [M + H]⁺ analysis I-8 (C1-8)

1.54 508.3/510.3 C 2.3 Derivatisation of Intermediates/Example Compounds C1 or (I) to Form Other Intermediates/Example Compounds G1 or (I).

2.3.1 Fmoc cleaving (Method J)

The Fmoc-protected compound C1 (e.g. C₁₋₃ or C₁₋₄) is combined with piperidine (5 equivalents) in DMF (10 mL/1 g of starting compound) and stirred for 1 h at RT. The mixture is evaporated down and the crude product is purified by column chromatography.

The following components G1 are obtained (Table 9):

TABLE 9 Intermediate t_(ret) method of (Example) Structure educt [min] [M + H]⁺ analysis G1-1 (I-9)

C1-3 1.39 477 K G1-2 (I-10)

C1-4 1.43 521 K 2.3.2 Amide Cleaving/Deacetylation (Method K)

C1-1 (1.22 g, 2.22 mmol) is stirred in conc. HCl (0.5 mL) for 15 min at 120° C. in a microwave reactor. The reaction mixture is made basic with concentrated ammonia, diluted with water and exhaustively extracted with DCM. The organic phase is washed with water, dried on magnesium sulphate, filtered and evaporated down. The crude product is purified by column chromatography.

The following components G1 are obtained (Table 10):

TABLE 10 Intermediate t_(ret) method of (Example) Structure educt [min] [M + H]⁺ analysis G1-3 (I-11)

C1-1 1.68 508 G G1-4 (I-12)

C1-2 0.36 467.2 C 3. Preparation of the Intermediates/Example Compounds C2 and G2 or (I)

3.1 General Synthesis of Intermediates F2 (Method L).

The preparation of 2-(hetero)arylamino-4-chloro-5-trifluoromethylpyrimidine derivatives F2 is carried out analogously to WO 2005/023780. The crude products obtained are optionally purified by chromatography.

The following components F2 are obtained (Table 11):

TABLE 11 t_(ret) Intermediate Structure [min] [M + H]⁺ method of analysis F2-1⁴

1.50 488.1 C F2-2⁵

0.95 549.0 C F2-3⁶

1.24 445.2 C F2-4⁷

1.68 516.2 C F2-5⁸

1.49 500.2 C F2-6⁹

1.09 401.4 B F2-7¹⁰

1.21 571.2 B F2-8¹¹

0.83 444.0 C F2-9¹²

1.58 502.2 C F2-10¹³

1.37 459.2 C F2-11⁸

1.59 502.2 C F2-12¹⁴

2.51 410   I F2-13

F2-14

2.2  459   I F2-15¹⁵

2.61 401   I F2-16

F2-19^(15,16)

2.03 431   O F2-20¹⁵

2.50 469   (M − H) P F2-21¹⁵

2.02 431   (M + H − tBu) O F2-22⁷

1.91 472   O F2-23¹⁵

1.61 469   (M − H) O F2-24^(15,16)

243 469   (M − H) P F2-25¹⁵

2.13 521   (M − H) N F2-26¹⁵

2.13 487   (M − H) N F2-27¹⁵

2.14 483   (M − H) N F2-28¹⁵

1.97 483   (M − H) O F2-29¹⁵

2.15 429   (M + H) − tBu N F2-30¹⁵

1.94 445   (M + H) − tBu O F2-31

F2-32

F2-33

⁴the educt aniline R²—NH₂ is prepared from the nitro compound analogously to WO 2006/021548 by reduction using standard methods ⁵the educt anliline R²—NH₂ is prepared according to US 2008/300242 ⁶the educt aniline R²—NH₂ is prepared analogously to WO 2002/006232 ⁷the educt aniline R²—NH₂ is prepared analogously to US 2008/300242 ⁸the educt aniline R²—NH₂ is prepared from 4-fluoro-2-methoxy-1-nitrobenzene analogously to WO 2006/021548 using standard methods ⁹the educt aniline R²—NH₂ is prepared according to WO 2006/021548 ¹⁰the educt aniline R²—NH₂ is prepared analogously to WO 2005/016894 ¹¹F2-10 is prepared from the corresponding aminobenzoic acid (cf. WO 2007/115999) by reaction with thionyl chloride and 1-methylpiperidin-4-amine using standard methods ¹²the educt anline R²—NH₂ is prepared from 2-ethoxy-4-fluoro-1-nitrobenzene analogously to WO 2006/021548 using standard methods ¹³the educt anline R²—NH₂ is prepared from 4-fluoro-2-methoxy-1-nitrobenzene and ethyl piperidine-4-carboxylate analogously to WO 2006/021548 using standard methods ¹⁴the educt aniline R²—NH₂ is prepared from the corresponding nitro compound by reduction ¹⁵the educt anline R²—NH₂ is prepared according to or analogously to the following method:

4-chloro-2-methoxy-nitrobenzene (2.0 g, 9.6 mmol) is taken up in 40 mL anhydrous dioxane in an argon atmosphere. 3-pyridineboric acid (1.77 g. 14.4 mmol) is added to this mixture, followed by degassed sodium carbonate solution (10 mL, 3M) and bistriphenylphosphine-palladium (II) chloride (337 mg, 48 mmol). The reaction mixture is stirred tor 16 h at 80° C. under an argon atmosphere. After further addition of sodium carbonate (3.2 g) and 0.1 eq palladium catalyst the mixture is stirred again for 4 h at 85° C. After cooling, the reaction mixture is poured onto water (100 mL), extracted 3 × with ethyl acetate (20 mL aliquots), the combined organic phases are dried on magnesium sulphate and evaporated down in vacuo. Chromatographic purification through silica gel with cyclohexane/ethyl acetate yields the coupling product. The coupling product obtained (2.04 g, 8.63 mmol) is taken up in glacial acetic acid (100 mL), mixed with platinum oxide (100 mg, 0.1 eq) and hydrogenated for 48 h at RT and 9 bar of H₂ pressure. The reaction mixture is filtered through Celite, the volatile constituents are eliminated in vacuo and the solution obtained is poured into saturated, aqueous sodium hydrogen carbonate solution (50 mL). It is extracted 3 × with ethyl acetate (30 mL aliquots), the combined organic phases are dried on magnesium sulphate, then after evaporation purified by chromatography (silica gel, cyclohexane/ethyl acetate) and the aniline is obtained. The aniline obtained (971 mg, 4.71 mmol) is taken up in dichloromethane (50 mL), di-tert-butylcarbonate (1.03 g, 4.71 mmol) is added and the reaction mixture is stirred for 3 h at RT. After concentration in vacuo the crude product of the Boc-protected aniline is obtained, which is further used directly. ¹⁶racemic representation of the structural formula always explicitly includes both configurations, i.e.

3.2 Derivatisation of Intermediates F2 to Form Further Intermediates F2. 3.2.1 Synthesis of Intermediate F2-17 (Boc Cleaving, Method M)

F2-17 (200 mg, 0.43 mmol) in anhydrous DCM (5 mL) is combined at 0° C. with TFA (30 equivalents) and stirred for 2 h at RT. The mixture is mixed with water, neutralised with 2 N NaOH and exhaustively extracted with DCM. The organic phase is washed with water, dried on magnesium sulphate, filtered and evaporated down.

3.2.2 Synthesis of intermediate F2-18 (reductive amination, method N)

F2-17 (156 mg, 0.43 mmol) in anhydrous DCM (10 mL) is combined with 37% aqueous formaldehyde solution (1.2 equivalents) and acetic acid (2.4 equivalents) and stirred for 30 min at RT. Sodium triacetoxyborohydride (1.4 equivalents) is added. The reaction mixture is stirred for 16 h and then evaporated down. The residue is taken up in EtOAc, washed with saturated sodium hydrogen carbonate solution and saturated saline solution, dried on magnesium sulphate, filtered and evaporated down. The crude product is optionally purified by column chromatography.

TABLE 12 method Inter- t_(ret) of mediate Structure [min] [M + H]⁺ analysis F2-17

1.5  359 I F2-18

1.53 373 I 3.3 General Synthesis of Intermediates/Example Compounds C2 or (I) Starting from Intermediates F2 (Method F).

The reaction of 4-chloropyrimidine components F2 with corresponding amines R⁴—NH₂ is carried out according to method F (cf. 2.1.1)

TABLE 13 Intermediate t_(ret) method of (Example) Structure [min] [M + H]⁺ analysis C2-1 (I-13)

1.11 614.4 C C2-2 (I-14)

0.82 571.2 C C2-3 (I-15)

1.35 642.4 C C2-4 (I-16)

1.17 654.4 C C2-5 (I-17)

1.35 656.4 C C2-6 (I-18)

1.22 642.3 C C2-7 (I-19)

1.31 656.4 C C2-8 (I-20)

1.14 628.4 C C2-9 (I-21)

1.10 613.4 C C2-10 (I-22)

2.13 546   I C2-11 (I-23)

2.41 592   K C2-12 (I-24)

2.24 611   I C2-13

1.30 536.2/ 538.2 C C2-14 (I-25)

1.87 703.3 G C2-15 (I-26)

1.76 675.3 G C2-16¹⁷ (I-261)

1.92 641   O C2-17 (I-262)

1.61 625   P C2-18 (I-263)

1.81 626   O C2-19 (I-264)

1.99 625   N C2-20¹⁷ (I-265)

2.24 625   P C2-21 (I-266)

2.03 677   N C2-22 (I-267)

2.03 643   N C2-23 (I-268)

2.02 639   N C2-24 (I-269)

1.87 639   O C2-25 (I-270)

2.03 639   N C2-26 (I-271)

1.83 655   O C2-27 (I-272)

C2-28 (I-273)

C2-29 (I-274)

C2-30 (I-275)

¹⁷racemic representation of the structural formula always explicitly includes both configurations, i.e.

3.4 Derivatisation of Intermediates/Example Compounds C2 or (I) to Form Other Intermediates/Example Compounds G2 or (I).

3.4.1 Boc cleaving (Method O)

C2-1 (2.0 g, 3.26 mmol) in anhydrous DCM (20 mL) is combined at 0° C. with TFA (5 mL) and stirred for 3 h at RT. The mixture is mixed with water, neutralised with 2 N NaOH and exhaustively extracted with DCM. The organic phase is washed with water, dried on magnesium sulphate, filtered and evaporated down. The crude product is optionally purified by column chromatography.

The following components G2 (Table 14) are prepared by this method (alternatively, the cleaving may be carried out hydrogenolytically if the Z protective group is used, method P):

TABLE 14 Intermediate t_(ret) method of (Example) Structure [min] [M + H]⁺ analysis G2-1 (I-27)

0.54 514.2 C G2-2 (I-28)

0.63 542.0 C G2-3 (I-29)

0.58 554.2 C G2-4 (I-30)

1.88 556   G G2-5 (I-31)

0.67 542.1 C G2-6 (I-32)

1.74 528.3 G G2-7 (I-33)

1.90 556.3 G G2-8 (I-34)

0.70 556.4 C G2-9 (I-35)

1.52 511   I G2-156¹⁸ (I-276)

1.67 541   O G2-157 (I-277)

1.58 525   P G2-158 (I-278)

1.59 526   O G2-159 (I-279)

1.17 525   P G2-160¹⁸ (I-280)

1.71 525   O G2-161 (I-281)

1.77 577   N G2-162 (I-282)

1.72 543   N G2-163 (I-283)

1.72 539   N G2-164 (I-284)

1.69 539   O G2-165 (I-285)

1.82 539   N G2-166 (I-286)

1.66 555   O G2-167 (I-287)

G2-168 (I-288)

G2-169 (I-289)

G2-170 (I-290)

¹⁸racemic representation of the structural formula always explicitly includes both configurations, i.e.

3.4.2 Ketal Cleaving (Method Q)

C2-2 (1.20 g, 2.10 mmol) in 6 N HCl (10 mL) and MeOH (5 mL) is stirred for 18 h at RT. After the addition of 1.5 mL concentrated HCl the mixture is stirred for a further 2 h at RT. The reaction mixture is made basic with concentrated ammonia, diluted with water and exhaustively extracted with DCM. The organic phase is washed with water, dried on magnesium sulphate, filtered and evaporated down. The crude product is optionally purified by column chromatography.

The following components G2 (Table 15) are prepared by this method:

TABLE 15 Intermediate t_(ret) method of (Example) Structure [min] [M + H]⁺ analysis G2-10 (I-36)

0.93 527.0 B G2-11 (I-37)

0.90 555.2 C 3.4.3 Alkylester Cleavage (Method R)

C2-9 (320 mg, 0.52 mmol) in THF (2 mL) and EtOH (0.5 mL) is combined with 1N NaOH (3 equiv.) and stirred for 16 h at RT. The reaction mixture is neutralised with 1N HCl, evaporated down to one third of the volume and divided between water and DCM. The aqueous phase is exhaustively extracted with DCM. The combined organic phase is washed with water, dried on magnesium sulphate, filtered and evaporated down. The crude product is optionally purified by column chromatography.

TABLE 16 Intermediate t_(ret) method of (Example) Structure [min] [M + H]⁺ analysis G2-12 (I-38)

0.83 585.4 C 3.4.4 Debenzylation (Method S)

C2-10 (155 mg, 0.27 mmol) is hydrogenated in the presence of Pd(OH)₂ in EtOH (6.5 mL) 16 h at RT under a hydrogen pressure of 1 bar. The reaction mixture is filtered and the filtrate is evaporated down.

TABLE 17 t_(ret) method of Intermediate Structure [min] [M + H]⁺ analysis G2-13

1.6 474 I 3.4.5 Benzylester Cleavage (Method T)

Benzylester cleavage on C2-11: The benzylester cleavage is carried out analogously to the debenzylation (method S, 3.4.4).

TABLE 18 t_(ret) method of Intermediate Structure [min] [M + H]⁺ analysis G2-14

1.89 502 K 3.4.6 by SUZUKI Coupling

3.4.6.1 SUZUKI Reaction (Method U)

N-Boc-1,2,5,6-tetrahydropyridine-4-boric acid pinacol ester (192 mg, 0.60 mmol), C2-13 (268 mg, 0.50 mmol), bis(triphenylphosphine)palladium(II)chloride (36 mg, 0.03 mmol) and sodium carbonate (159 mg, 1.5 mmol) are stirred in water (1.5 mL) and dioxane (3 mL) under argon for 20 min at 120° C. in a microwave reactor. The reaction mixture is combined with EtOH (80 mL), filtered and used directly in the next step.

TABLE 19 Intermediate t_(ret) method of (Example) Structure [min] [M + H]⁺ analysis G2-15 (I-39)

1.47 639.4 C 3.4.6.2 Reduction/Hydrogenation (Method V)

The reaction mixture from the previous step is hydrogenated in the H-Cube throughflow reactor (Thalos Nano, 40° C., flow: 1 mL/min, Full H₂ Mode, catalyst: 10% Pd/C). The reaction mixture is evaporated down.

TABLE 20 Intermediate t_(ret) method of (Example) Structure [min] [M + H]⁺ analysis G2-16 (I-40)

1.43 641.4 C 3.4.6.3 Boc Cleaving (Cf. Method 0, 3.4.1)

The cleaving der Boc-protective group is carried out analogously to method O.

TABLE 21 intermediate t_(ret) method of (Example) Structure [min] [M + H]⁺ analysis G2-17 (I-41)

2.25 541.3 G 4. Preparation of Further Example Compounds (I) by Derivatisation of Example Compounds/Intermediates C1 or C2, G1 or G2 and (I) 4.1 Acylation 4.1.1 General synthesis: acylation with acid chlorides (Method W)

The corresponding compound C1, C2, G1 or G2 is taken up in anhydrous DCM, combined with the acid chloride (1.4 equivalents) and triethylamine (3 equivalents) and stirred for 3 h at RT. The reaction mixture is evaporated down, the residue is taken up in DMSO and purified by preparative HPLC-MS. The fractions containing the reaction product are freeze-dried.

4.1.2 General Synthesis: Amide Coupling with Acids (Method X)

The starting compound (50 mg) in anhydrous DMSO (1 mL) is combined with TBTU (1.5 equivalents), triethylamine (1.5 equivalents) and the corresponding carboxylic acid (5 equivalents) and stirred for 5 h at RT. The reaction mixture is purified by preparative HPLC-MS. The fractions containing the reaction product are freeze-dried.

(Acid components which in turn contain a Boc-protected amino functionality are deprotected in a subsequent step by reacting with TFA or HCl.)

The following Example compounds (Table 22) are obtained by acylation of corresponding precursors. The Example compounds obtained first may be optionally be deprotected by conventional methods and/or reacted by further standard reactions (e.g. direct alkylation, reductive alkylation, carboxylic acid amide formation, sulphonamide formation, acylation etc.) to form other Example compounds.

TABLE 22 t_(ret) method of # Structure educt [min] [M + H]⁺ analysis I-42 (G1-5)

G1-2 2.75 608 H I-43 (G1-6)

G1-1 2.7 562 H I-44 (G1-7)

G1-1 3.59 674 H I-45 (G1-8)

G1-1 3.47 635 H I-46 (G1-9)

G1-1 3.56 648 H I-47 (G1-10)

G1-1 3.62 661 H I-48 (G1-11)

G1-1 3.13 585 H I-49 (G1-12)

G1-1 2.72 574 H I-50 (G1-13)

G1-1 2.62 534 H I-51 (G1-14)

G1-1 2.62 548 H I-52 (G1-15)

G1-1 2.61 560 H I-53 (G1-16)

G1-2 3.1 648 H I-54 (G1-17)

G1-2 3.26 609 H I-55 (G1-18)

G1-2 2.75 620 H I-56 (G1-19)

G1-2 2.7 606 H I-57 (G1-20)

C1-6 1.87 620.2/ 622.2 G I-58 (G1-21)

1.86 592.3 G I-59 (G1-22)

G1-3 1.91 633.3 G I-60 (G1-23)

G1-3 1.81 633.3 G I-61 (G1-24)

G1-3 1.74 648.2 G I-62 (G1-25)

G1-3 1.80 593.3 G I-63 (G1-26)

G1-3 1.84 633.3 G I-64 (G1-27)

G1-3 1.87 621.3 G I-65 (G1-28)

G1-3 1.72 633.3 G I-66 (G1-29)

G1-4 1.16 552.2 G I-67 (G1-30)

C1-5 1.40 562.3 G I-68 (G1-31)

1.90 636.2/ 638.3 G I-69 (G1-32)

C1-5 1.37 576.2 G I-70 (G2-18)

G2-1 1.64 556.3 G I-71 (G2-19)

G2-1 1.74 585.3 G I-72 (G2-20)

G2-1 1.89 586.3 G I-73 (G2-21)

G2-8 2.02 614.3 G I-74 (G2-22)

G2-9 3.16 624 H I-75 (G2-23)

G2-9 3.05 596 H I-76 (G2-24)

G2-5 1.88 613.3 G I-77 (G2-25)

G2-5 1.78 584.3 G I-78 (G2-26)

G2-6 1.75 570.3 G I-79 (G2-27)

G2-7 1.88 598.3 G I-80 (G2-28)

G2-3 1.76 596 G I-81 (G2-29)

G2-3 1.86 625.3 G I-82 (G2-30)

G2-3 1.91 612.3 G I-83 (G2-31)

G2-5 1.80 614.3 G I-84 (G2-32)

G2-5 1.96 627.3 G I-85 (G2-33)

G2-5 1.84 628 G I-86 (G2-34)

G2-5 1.93 655.3 G I-87 (G2-35)

G2-5 1.93 667.2 G I-88 (G2-36)

G2-5 1.84 682.3 G I-89 (G2-37)

G2-5 1.88 641.3 G I-90 (G2-38)

G2-5 1.91 667.2 G I-91 (G2-39)

G2-1 1.73 599.2 G I-92 (G2-40)

G2-1 1.82 627.2 G I-291¹⁹ (G1-63)

C1-7 1.34 632/634 P I-292 (G1-64)

C1-5 1.32 563/565 P I-293 (G1-65)

C1-5 1.33 562/564 P I-294 (G1-66)

C1-5 1.24 534/536 P I-295 (G1-67)

C1-5 1.32 588/590 P I-296 (G1-68)

C1-19 1.31 565/567 P I-297 (G1-69)

C1-5 1.35 577/579 P I-298 (G1-70)

C1-5 1.27 549/551 P I-299 (G1-71)

G1-1 1.29 574/576 P I-300 (G1-72)

C1-19 1.38 593/595 P ¹⁹racemic representation of the structural formula always explicitly includes both configurations, i.e.

4.2 Reductive Amination 4.2.1 General Synthesis: Reductive Amination on Amines C1, C2, G1 or G2 (Method Y)

The corresponding compound C1, C2, G1 or G2 is taken up in anhydrous NMP, combined with the carbonyl compound (3 equivalents) and sodium triacetoxyborohydride (2.9 equivalents) and stirred for 1.5 h at RT. The reaction mixture is combined with formic acid and purified by preparative HPLC-MS. The fractions containing the reaction product are freeze-dried.

The following Example compounds (Table 23) are obtained by reductive amination of the corresponding precursors. The Example compounds obtained first may optionally be deprotected by conventional methods and/or reacted by further standard reactions (e.g. direct alkylation, reductive alkylation, carboxylic acid amide formation, sulphonamide formation, acylation etc.) to form further Example compounds.

TABLE 23 t_(ret) method of # Structure educt [min] [M + H]⁺ analysis I-93 (G1-33)

G1-1 2.59 533 K I-94 (G1-34)

1.65 492.0 G I-95 (G1-35)

G1-3 1.80 592.3 G I-96 (G1-36)

G1-3 2.01 562.3 G I-97 (G1-37)

G1-3 1.77 522.2 G I-98 (G1-38)

G1-3 1.95 550 G I-99 (G1-39)

G1-3 1.85 536 G I-100 (G1-40)

G1-3 1.94 521.3 G I-101 (G1-41)

G1-3 1.98 562.3 G I-102 (G1-42)

G1-4 1.17 481.2 G I-103 (G1-43)

C1-6 1.94 549.3/ 551.2 G I-104 (G2-41)

G2-5 1.86 556.3 G I-105 (G2-42)

G2-8 2.09 640.3 G I-106 (G2-43)

G2-8 2.14 598.3 G I-107 (G2-44)

G2-8 2.01 584.3 G I-108 (G2-45)

G2-8 1.92 570.3 G I-109 (G2-46)

G2-8 2.15 610.3 G I-110 (G2-47)

G2-1 1.66 639.3 G I-111 (G2-48)

G2-1 1.95 639.3 G I-112 (G2-49)

G2-1 1.91 637.3 G I-113 (G2-50)

G2-1 1.74 636.3 G I-114 (G2-51)

G2-1 1.86 625.3 G I-115 (G2-52)

G2-1 1.80 681.3 G I-116 (G2-53)

G2-1 1.89 556.3 G I-117 (G2-54)

G2-1 1.91 611.3 G I-118 (G2-55)

G2-1 1.77 598.3 G I-119 (G2-56)

G2-1 1.71 528.3 G I-120 (G2-57)

G2-1 1.80 605.3 G I-121 (G2-58)

G2-1 1.69 641.3 G I-122 (G2-59)

G2-1 1.82 655.3 G I-123 (G2-60)

G2-1 1.57 668.3 G I-124 (G2-61)

G2-1 1.66 704.3 G I-125 (G2-62)

G2-1 1.55 675.3 G I-126 (G2-63)

G2-4 2.00 640.3 G I-127 (G2-64)

G2-4 1.97 570 G I-128 (G2-65)

G2-4 2.16 598.3 G I-129 (G2-66)

G2-4 2.06 584.3 G I-130 (G2-67)

G2-4 2.07 653.3 G I-131 (G2-68)

G2-8 1.97 610.5 G I-132 (G2-69)

G2-8 1.82 653.3 G I-133 (G2-70)

1.43 527 I I-134 (G2-71)

G2-9 3.09 553 H I-135 (G2-72)

G2-5 2.00 639.3 G I-136 (G2-73)

G2-5 2.03 584.3 G I-137 (G2-74)

G2-2 2.17 584.3 G I-138 (G2-75)

G2-6 1.82 542.3 G I-139 (G2-76)

G2-6 2.00 570.3 G I-140 (G2-77)

G2-6 1.91 556.3 G I-141 (G2-78)

G2-6 1.76 584.3 G I-142 (G2-79)

G2-7 1.96 570.3 G I-143 (G2-80)

G2-7 2.13 598.3 G I-144 (G2-81)

G2-7 2.04 584.3 G I-145 (G2-82)

G2-7 2.06 653.3 G I-146 (G2-83)

G2-7 1.90 612.3 G I-147 (G2-84)

G2-3 1.95 651.3 G I-148 (G2-85)

G2-3 2.05 608.3 G I-149 (G2-86)

G2-3 2.04 608.3 G I-150 (G2-87)

G2-3 1.86 638.3 G I-151 (G2-88)

G2-3 1.86 568.3 G I-152 (G2-89)

G2-3 1.99 596.3 G I-153 (G2-90)

G2-3 1.94 582.3 G I-154 (G2-91)

G2-3 1.80 610 G I-155 (G2-92)

G2-5 2.09 596.3 G I-156 (G2-93)

G2-5 1.81 598 G I-157 (G2-94)

G2-5 1.95 570.3 G I-158 (G2-95)

G2-5 1.82 667.3 G I-159 (G2-96)

G2-17 2.29 583.3 G I-160 (G2-97)

1.78 554.2 G I-161 (G2-98)

1.79 489.3 G I-162 (G2-99)

G2-5 2.08 596.3 G I-163 (G2-100)

G2-5 2.06 697.2 G I-164 (G2-101)

G2-5 2.07 622.2 G I-165 (G2-102)

G2-1 1.94 568.2 G I-166 (G2-103)

G2-1 1.92 669.2 G I-301²⁰ (G2-171)

G2-156 1.58 613 P I-302 (G2-172)

G2-17 1.38 613 M I-303 (G2-173)

G2-157 1.53 597 M I-304 (G2-174)

G2-5 1.45 614 P I-305 (G2-175)

G2-158 1.42 598 P I-306²⁰ (G2-176)

G2-160 1.52 597 M I-307 (G2-177)

G2-158 1.36 540 P I-308 (G2-178)

G2-159 1.46 539 P I-309 (G2-179)

G2-159 1.36 597 M I-310 (G2-180)

G2-161 1.41 649 M I-311 (G2-181)

G2-162 1.40 615 M I-312 (G2-182)

G2-163 1.39 611 M I-313 (G2-183)

G2-164 1.33 611 M I-314 (G2-184)

G2-165 1.42 611 M I-315 (G2-185)

G2-166 1.33 627 P I-316²⁰ (G1-73)

C1-7 1.51 647/649 P I-317 (G1-74)

C1-10 1.38 608/610 P I-318²⁰ (G1-75)

C1-7 2.07 607/609 M I-319 (G1-76

C1-7 1.51 (4.16) 607/609 M (Q) I-320 (G1-77)

C1-7 1.51 (5.02) 607/609 M (Q) I-321 (G1-78)

C1-11 1.41 624/626 P I-322²⁰ (G1-79)

C1-12 1.54 623/625 P I-323 (G1-80)

C1-13 2.14 623/625 M I-324 (G1-81)

C1-14 1.91 607/609 M I-325²⁰ (G1-82)

C1-9 1.47 633/635 P I-326 (G1-83)

C1-5 1.50 603/605 P I-327²⁰ (G1-84)

C1-17 1.38 579/581 M I-328²⁰ (G1-85)

C1-18 1.49 563/565 P I-329²⁰ (G1-86)

C1-18 1.58 603/605 P I-330 (G1-87)

C1-20 1.27 506/508 P I-331 (G1-88)

C1-19 1.54 579/581 M I-332 (G1-89)

C1-5 1.42 505/507 A I-333²⁰ (G1-90)

C1-23 1.44 589/591 P I-334 (G1-91)

C1-21 1.31 563/565 M I-335 (G1-92)

G1-3 1.4  580/582 P I-336 (G1-93)

C1-20 1.37 564/566 P I-337 (G1-94)

C1-26 1.36 581/583 M I-338 (G1-95)

C1-27 1.35 577/579 M I-339 (G1-96)

C1-28 1.33 577/579 M I-340 (G1-97)

C1-29 1.46 633/635 M I-341 (G1-98)

C1-30 1.27 593/595 M I-342 (G1-99)

C1-31 1.37 615/617 M I-343 (G2-186)

G2-167 I-344²⁰ (G2-187)

G2-168 I-345²⁰ (G2-188)

G2-169 I-346²⁰ (G2-189)

G2-170 I-347²⁰ (G1-100)

I-348²⁰ (G1-101)

I-349²⁰ (G1-102)

²⁰racemic representation of the structural formula always explicitly includes both configurations, i.e.

4.2.2 General Synthesis: Reductive Amination on Carbonyl Compounds G1 or G2 (cf. Method Y)

Reductive amination using G1 or G2 with a carbonyl substructure and amines is carried out according to method Y.

The following Example compounds (Table 24) are obtained by reductive amination of corresponding precursors. The Example compounds obtained first may optionally be deprotected by conventional methods and/or be reacted by further standard reactions (e.g. direct alkylation, reductive alkylation, carboxylic acid amide formation, sulphonamide formation, acylation etc.) to obtain further Example compounds.

TABLE 24 method t_(ret) of # Structure educt [min] [M + H]⁺ analysis I-167 (G2-104)

G2-11 1.9  614.3 G I-168 (G2-105)

G2-11 2.04 642.3 G I-169 (G2-106)

G2-11 1.84 614   G I-170 (G2-107)

G2-11 2.02 654.3 G I-171 (G2-108)

G2-11 1.90 626.3 G I-172 (G2-109)

G2-11 1.83 626.3 G I-173 (G2-110)

G2-11 2.07 642.3 G I-174 (G2-111

G2-11 1.84 626.3 G I-175 (G2-112)

G2-11 1.98 628.3 G I-176 (G2-113)

G2-11 2.04 596   G I-177 (G2-114)

G2-11 1.84 640.3 G I-178 (G2-115)

G2-10 1.92 613.3 G I-179 (G2-116)

G2-10 1.78 586.3 G I-180 (G2-117)

G2-11 2.14 610.3 G I-181 (G2-118)

G2-11 2.00 584.3 G I-182 (G2-119)

G2-10 2.00 639.3 G I-183 (G2-120)

G2-10 2.09 613.3 G I-184 (G2-121)

G2-10 1.88 556.3 G I-185 (G2-122)

G2-10 2.09 627.3 G I-186 (G2-123)

G2-10 1.72 586.3 G I-187 (G2-124)

G2-10 1.89 542.3 G I-188 (G2-125)

G2-10 1.72 612.3 G I-189 (G2-126)

G2-10 2.03 582.3 G I-190 (G2-127)

G2-10 1.92 637.5 G I-191 (G2-128)

G2-10 1.66 572.3 G I-192 (G2-129)

G2-10 1.89 626.3 G I-193 (G2-130)

G2-10 1.83 694.3 G I-194 (G2-131)

G2-10 1.86 599.3 G I-195 (G2-132)

G2-10 1.84 621.3 G I-196 (G2-133)

G2-10 1.76 598.3 G I-197 (G2-134)

G2-10 1.85 600.3 G I-198 (G2-135)

G2-10 1.88 639.3 G I-199 (G2-136)

G2-10 2.00 632.3 G I-200 (G2-137)

G2-10 1.74 681.3 G I-201 (G2-138)

G2-10 1.69 639.3 G I-202 (G2-139)

G2-10 1.73 611.3 G 4.3 Sulphonylation 4.3.1 General Synthesis: Sulphonylation (Method Z)

The corresponding compound C1, C2, G1 or G2 is taken up in anhydrous DCM, combined with the sulphonic acid chloride (1.4 equivalents) and triethylamine (3 equivalents) and stirred for 3 h at RT. The reaction mixture is evaporated down, the residue is taken up in DMSO and purified by preparative HPLC-MS. The fractions containing the reaction product are freeze-dried.

The following Example compounds (Table 25) are obtained by sulphonylation of corresponding precursors. The Example compounds obtained first may optionally be deprotected by conventional methods and/or reacted by further standard reactions (e.g. direct alkylation, reductive alkylation, carboxylic acid amide formation, sulphonamide formation, acylation etc.) to form further Example compounds.

TABLE 25 method t_(ret) of # Structure educt [min] [M + H] analysis I-203 (G1-44)

C1-5 1.38 569.3 G 4.4 Direct alkylation 4.4.1 General Synthesis: Alkylation (Method AA)

The corresponding compound C1, C2, G1 or G2 is taken up in anhydrous DMSO, combined with the alkylhalide (1.2 equivalents) and triethylamine (3 equivalents) and stirred for 12 h at RT. The reaction mixture is purified by preparative HPLC-MS. The fractions containing the reaction product are freeze-dried.

The following Example compounds (Table 26) are obtained by direct alkylation of corresponding precursors. The Example compounds obtained first may optionally be deprotected by conventional methods and/or reacted by further standard reactions (e.g. direct alkylation, reductive alkylation, carboxylic acid amide formation, sulphonamide formation, acylation etc.) to form further Example compounds.

TABLE 26 method t_(ret) of # Structure educt [min] [M + H]⁺ analysis I-204 (G1-45)

G1-1  4.91 535 J I-205 (G1-46)

G1-1  2.57 522 H I-206 (G1-47)

G1-1  2.58 548 I I-207 (G1-48)

G1-1  2.65 583 I I-208 (G1-49)

G1-2  2.73 579 H I-209 (G1-50)

G1-2  2.63 565 H I-210 (G1-51)

G1-2  2.73 593 J I-211 (G1-52)

G1-1  2.63 549 H I-212 (G1-53)

G1-2  2.71 581 H I-213 (G1-54)

G1-1  2.65 537 H I-214 (G1-55)

C1-6  1.82 579.2/581.3 G I-215 (G1-56)

G1-4  1.19 525.3 G I-216 (G1-57)

C1-5  1.35 597.3 G I-217 (G1-58)

C1-5  1.35 535.2 G I-218 (G1-59)

C1-5  1.36 549.3 G I-219 (G1-60)

C1-5  1.36 562.3 G I-220 (G1-61)

C1-5  1.31 548.3 G I-221 (G1-62)

C1-6  2.00 593.2/595.2 G I-222 (G2-140)

G2-1  1.77 560.3 G I-223 (G2-141)

G2-1  1.61 558.3 G I-224 (G2-142)

G2-1 1.75 572.3 G I-350²¹ (G2-190)

 G2-156 1.49 599 P I-351²¹ (G2-191)

 G2-156 1.39 585 P I-352 (G2-192)

 G2-159 1.46 583 P I-353 (G2-193)

G2-5  1.39 600 P I-354²¹ (G2-194)

 G2-160 1.40 569 P I-355 (G2-195)

 G2-159 1.38 569 P I-356²¹ (G2-196)

 G2-160 1.48 583 P I-357²¹ (G1-103)

C1-9  1.39 579/581 P I-358²¹ (G1-104)

C1-9  1.29 565/567 P I-359²¹ (G1-105)

C1-7  1.47 593/595 P I-360²¹ (G1-106)

C1-12 1.47 609/611 P I-361²¹ (G1-107)

C1-12 1.37 595/597 P I-362 (G1-108)

C1-7  1.63 (7.54) 593/595 P (R) I-363 (G1-109)

C1-7  1.63 (8.69) 593/595 P (R) I-364²¹ G1-110)

C1-7  1.62 579/581 P I-365²¹ (G1-111)

C1-9  1.32 592/594 P I-366²¹ (G1-112)

C1-7  1.36 606/608 P I-367 (G1-113)

C1-15 1.5  607/609 P I-368²¹ (G1-114)

C1-16 1.49 607/609 P I-369 (G1-115)

C1-11 1.37 610/612 P I-370 (G1-116)

C1-5  1.36 562/564 P I-371²¹ (G1-117)

C1-17 1.45 565/567 P I-372²¹ (G1-118)

C1-17 1.34 551/553 P I-373²¹ (G1-119)

C1-18 1.41 549/551 P I-374 (G1-120)

C1-19 1.41 546/548 P I-375 (G1-121)

C1-5  1.38 530/532 P I-376 (G1-122)

C1-21 1.98 549/551 M I-377 (G1-123)

C1-5  1.32 563/565 M I-378 (G1-124)

C1-22 1.38 577/579 M I-379²¹ (G1-125)

C1-23 1.30 548/550 P I-380²¹ (G1-126)

C1-23 1.44 535/537 P I-381²¹ (G1-127)

C1-23 1.25 521/523 P I-382²¹ (G1-128)

C1-18 1.32 535/537 P I-383²¹ (G1-129)

C1-18 1.32 562/564 P I-384²¹ (G1-130)

C1-24 1.46 563/565 P I-385 (G1-131)

C1-22 1.47 563/565 P I-386 (G1-132)

C1-25 1.34 566/568 P ²¹racemic representation of the structural formula always explicitly includes both configurations, i.e.,

4.5 Amide Coupling to Carboxylic Acid Components G1 or G2 (Cf. Method X)

The amide coupling is carried out analogously to method X (i.e. with TBTU), except that in this case the corresponding compound G1 or G2 has the carboxyl function and is reacted with an amine.

The following Example compounds (Table 27) are obtained by amide coupling of corresponding precursors. The Example compounds obtained first may optionally be deprotected by conventional methods and/or reacted by further standard reactions (e.g. direct alkylation, reductive alkylation, carboxylic acid amide formation, sulphonamide formation, acylation etc.) to form further Example compounds.

TABLE 27 method t_(ret) of # Structure educt [min] [M + H]⁺ analysis I-225 (G2-143

G2-14 1.97 612.3 G I-226 (G2-144)

G2-12 1.75 681.5 G I-227 (G2-145)

G2-12 1.58 598.5 G I-228 (G2-146)

G2-14 1.77 598.3 G I-229 (G2-147)

1.82 584.2 G I-230 (G2-148)

G2-12 1.70 612.5 G I-231 (G2-149)

1.90 612.3 G I-232 (G2-150)

1.80 570.3 G I-233 (G2-151)

1.91 626.2 G I-234 (G2-152)

G2-14 3.86 571 H I-235 (G2-153)

1.19 525.3 G 4.6 Derivatisation on Phenolic Components G1 or G2 (Method AB)

The corresponding compound G1 or G2, an organic halide (e.g. alkylhalide, 0.9 equivalents) and potassium carbonate (1.9 equivalents) are stirred in DMF for 48 h at 100° C. The reaction mixture is divided between DCM and saturated saline solution and the aqueous phase is exhaustively extracted. The organic phase is dried on sodium sulphate, filtered and evaporated down. The crude product is purified by preparative HPLC. The fractions containing the reaction product are freeze-dried.

Alternatively derivatisation may also be carried out on the phenolic hydroxyl function by MITSONOBU reaction.

The following Example compounds (Table 28) are obtained by alkylation of corresponding precursors. The Example compounds obtained first may optionally be deprotected by conventional methods and/or reacted by further standard reactions (e.g. direct alkylation, reductive alkylation, carboxylic acid amide formation, sulphonamide formation, acylation etc.) to form further Example compounds.

TABLE 28 method t_(ret) of # Structure educt [min] [M + H]⁺ analysis I-236 (G2-154)

G2-13 1.97 612.3 G I-237²² (G2-155)

G2-10 1.63 529.3 G ²²synthesis by reduction of G2-10

The following Examples describe the biological activity of the compounds according to the invention, without restricting the invention to these Examples.

Compounds of general formula (I) are characterised by their many possible applications in the therapeutic field. Particular mention should be made of those applications in which the inhibiting effect on the proliferation of cultivated human tumour cells but also on the proliferation of other cells such as endothelial cells, for example, are involved.

Insulin-Like Growth Factor-1 Receptor (IGF-1R)-Kinase Assay

The kinase activity is measured by DELFIA® assay (dissociation-enhanced lanthanide fluorescence immunoassay, Perkin Elmer). The cytoplasmic kinase domain of human IGF-1R (amino acids 964-1370) is expressed as a fusion protein with a glutathione-S-transferase tag (IGF-1R-GST) in High Five™ Cells (Invitrogen). Enzyme activity is measured in the presence of substances and a control substance. Poly-glutamate-tyrosine peptide (pEY, Sigma Aldrich) and biotinylated pEY (bio-pEY) are used as reaction substrates.

10 μL of substance in 25% DMSO are mixed with 30 μL of of IGF-1R-GST solution (67 mM HEPES pH 7.4, 15 μg/mL pEY, 1.7 μg/mL bio-pEY, 13.3 mM MgCl₂, 3.3 mM dithiothreitol, 0.0033% Brij 35, 2 ng IGF-1R-GST) in 96-well plates. The reactions are started with 10 μL of a 750 μM ATP solution. After 40 min at RT the reactions are stopped with 50 μL of stop solution (250 mM EDTA, 20 mM HEPES pH 7.4). 90 μL from each reaction are transferred onto streptavidin-coated 96-well plates. After 120 min incubation at RT the plates are washed three times with 200 μL phosphate-buffered saline (PBS) per well. The plates are incubated for 60 min with 100 μL of europium-coupled antibody against phospho-tyrosine (diluted 1/2000 in Perkin Elmer DELFIA assay buffer) per well. The plates are washed three times with 200 μL per well of DELFIA washing buffer. 100 μL DELFIA Enhancement Solution (Perkin Elmer) is added to each well, and the plates are incubated for 10 min. The fluorescence signal is measured with a Wallac Victor TRF Reader. IC₅₀ values for the inhibition of the IGF-1R-kinase activity are calculated using the programmes Fifty (Version 2) and GraphPad (Version 3.0).

Table 29 shows the IC₅₀ values of the example compounds determined using the above assay.

TABLE 29 IGF1R # IC₅₀[nM] I-2 21 I-7 0.69 I-8 28 I-11 2 I-25 7 I-26 9 I-30 3 I-31 0.7 I-32 3 I-33 0.6 I-41 0.2 I-42 0.79 I-43 7 I-44 25 I-45 23 I-46 29 I-47 38 I-48 7 I-49 5 I-50 3 I-51 2 I-52 7 I-53 6 I-54 7 I-55 1 I-56 2 I-57 0.76 I-58 1 I-59 4 I-60 3 I-61 3 I-62 1 I-63 2 I-64 2 I-65 2 I-66 6 I-67 15 I-68 0.4 I-69 1 I-70 21 I-71 50 I-72 72 I-73 29 I-74 2 I-75 2 I-76 11 I-77 3 I-78 30 I-79 4 I-80 47 I-81 81 I-82 65 I-83 5 I-84 0.3 I-85 9 I-86 1 I-87 3 I-88 9 I-89 0.18 I-90 0.32 I-91 6 I-92 9 I-93 5 I-94 14 I-95 16 I-96 3 I-97 2 I-98 2 I-99 2 I-100 2 I-101 2 I-102 4 I-103 0.69 I-104 0.1 I-105 2 I-106 0.08 I-107 0.62 I-108 0.93 I-109 0.87 I-110 8 I-111 18 I-112 5 I-113 3 I-114 4 I-115 10 I-116 10 I-117 9 I-118 11 I-119 11 I-120 49 I-121 16 I-122 15 I-123 12 I-124 12 I-125 15 I-126 3 I-127 3 I-128 2 I-129 2 I-130 2 I-131 0.33 I-132 0.6 I-133 13 I-134 1 I-135 0.57 I-136 2 I-137 65 I-138 13 I-139 8 I-140 11 I-141 19 I-142 0.55 I-143 1 I-144 0.81 I-145 0.67 I-146 4 I-147 5 I-148 3 I-149 2 I-150 3 I-151 2 I-152 3 I-153 2 I-154 13 I-155 1 I-156 4 I-157 0.61 I-158 2 I-159 0.41 I-160 4 I-161 0.96 I-162 2 I-163 10 I-164 14 I-165 4 I-166 11 I-167 0.2 I-168 0.2 I-169 0.26 I-170 0.33 I-171 0.38 I-172 0.4 I-173 0.46 I-174 0.81 I-175 0.87 I-176 0.98 I-177 1 I-178 2 I-179 2 I-180 2 I-181 2 I-182 3 I-183 3 I-184 4 I-185 4 I-186 4 I-187 4 I-188 5 I-189 5 I-190 6 I-191 6 I-192 6 I-193 7 I-194 7 I-195 7 I-196 8 I-197 9 I-198 11 I-199 11 I-200 13 I-201 20 I-202 24 I-203 14 I-204 2 I-205 2 I-206 5 I-207 10 I-208 0.68 I-209 1 I-210 0.47 I-211 3 I-212 3 I-213 4 I-214 0.62 I-215 12 I-216 2 I-217 1 I-218 1 I-219 2 I-220 2 I-221 0.98 I-222 32 I-223 18 I-224 18 I-225 2 I-226 2 I-227 5 I-228 8 I-229 12 I-230 13 I-231 15 I-232 47 I-233 58 I-234 8 I-235 14 I-236 0.51 I-237 21 I-238 1.0 I-254 2.2 IGF1R # IC50 [nM] I-291 6.0 I-292 5.0 I-293 10.0 I-294 7.0 I-295 4.0 I-296 1.0 I-297 9.0 I-298 7.0 I-299 8.0 I-300 11.0 I-301 1.6 I-302 0.6 I-303 0.2 I-304 1.0 I-305 2.0 I-306 1.0 I-307 1.0 I-308 0.8 I-309 1.0 I-310 5.0 I-311 15.0 I-312 27.0 I-313 0.5 I-314 5.0 I-315 1.9 I-316 2.0 I-317 6.0 I-318 0.4 I-319 2.0 I-320 0.9 I-321 2.0 I-322 0.5 I-323 0.9 I-324 0.1 I-325 2.0 I-326 2.0 I-327 1.0 I-328 1.0 I-329 2.0 I-330 3.0 I-331 1.0 I-332 1.0 I-333 2.0 I-334 0.4 I-335 3.0 I-336 4.0 I-337 9.0 I-339 2.1 I-340 11.0 I-341 0.9 I-342 3.0 I-350 0.5 I-351 0.5 I-352 0.8 I-353 2.0 I-354 1.0 I-355 0.5 I-356 0.8 I-357 0.7 I-358 0.7 I-359 0.5 I-360 0.6 I-36I 0.4 I-362 0.3 I-363 2.0 I-364 0.6 I-365 1.0 I-366 2.0 I-367 3.0 I-368 2.0 I-369 2.0 I-370 2.0 I-371 0.8 I-372 0.8 I-373 0.4 I-374 11.0 I-375 9.0 I-376 0.6 I-377 0.9 I-378 6.0 I-379 6.0 I-380 2.0 I-381 0.9 I-382 1.0 I-383 2.0 I-384 6.0 I-385 4.0 I-386 3.0 Cellular IGF-1R-Phosphorylation Assay

The activity of substances against the phosphorylation of IGF-1R in activated cells is measured as follows: mouse fibroblast cells (transfected with human IGF-1R, Fibro-hIGF-1R) are cultivated in standard medium (DMEM, 10% foetal calf serum (FCS, Gibco), 1×MEM Non-Essential Amino Acids (NEAA, Gibco), 7.5% sodium hydrogen carbonate (Gibco) and 0.3 mg/mL Puromycin (Sigma)) in a humid incubator at 37° C. with 5 CO₂/95% air.

10000 Fibro-hIGF-1R cells per well in 200 μL of standard medium are seeded into 96-well plates and cultivated overnight. The next day, the medium is suction filtered and the cells are cultivated in 90 μL serum-reduced medium (DMEM, 0.5% FCS, 1×MEM NEAA, 7.5% sodium hydrogen carbonate) for a further 24 h. 10 μL of substance solution (diluted in serum-reduced medium) is added thereto, and the cells are incubated for a further 120 min in the incubator. The phosphorylation of IGF-1R is activated for 30 min by the addition of IGF-1 (20 ng/mL in serum-reduced medium). All further incubations are carried out at RT. The supernatant is suction filtered from the wells, and the cells are fixed in 100 μL per well of 4% paraformaldehyde (diluted in PBS). The supernatant in the well is suction filtered and the cells are permeabilised for 5 min in 300 μL per well of 0.1% TritonX-100 (diluted in PBS). The supernatants are suction filtered once again and the cells are incubated for 20 min in quenching buffer (PBS with 0.1% TritonX-100 and 1.2 hydrogen peroxide), to inhibit the endogenous peroxidase of the cells. The cells are washed for 5 min with 300 μL per well of PBS with 0.1% TritonX-100 and then incubated for 60 min with 100 μL per well of blocking buffer (PBS with 0.1% TritonX-100 and 5% Bovine Serum Albumin (BSA)). The blocking buffer is exchanged for 50 μL of the first antibody buffer (1/1000 dilute anti-phospho-IGF-1 receptor β (Tyr1135/1136)/insulin receptor β (Tyr1150/1151) (19H7) rabbit monoclonal antibody from Cell Signaling Technology in blocking buffer) and the plates are incubated overnight at 4° C. The next day the plates are washed for 5 min with 300 μL PBS/0.1% TritonX-100 at RT and then incubated for 60 min with 50 μL per well of the second antibody buffer (1/500 diluted Goat Anti-Rabbit Immunoglobulin-Horseradish Peroxidase (HRP) (Dako) in blocking buffer) at RT. The plates are washed first for 5 min with 300 μL PBS/0.1% TritonX-100 and then for a further 5 min with 300 μL PBS at RT. The plates are developed for 10 min with 100 μL per well of a peroxidase solution (1:1 mixture of TMB Peroxidase Substrate and Peroxidase Solution B from Kirkegaard & Perry Laboratories, Inc.). The reactions are stopped with 100 μL per well of stop solution (1M phosphoric acid). The absorbance in each well is measured at 450 nm with a SpectraMax Absorbance Reader. EC₅₀ values for inhibiting the phosphorylation of the IGF-1R in activated cells are calculated using the programmes Fifty (Version 2) and GraphPad (Version 3.0).

Compounds (I) according to the invention generally display a good inhibitory effect in the cellular assay described above, i.e. for example an EC₅₀ value of less than 5 μmol/L, often less than 3 μmol/L.

Cell Proliferation Assays

Compounds were tested for their anti-proliferative effects in the TC-71 (Ewing's sarcoma) and HCT 116 (colorectal carcinoma) cancer cell lines in vitro. Published scientific data has described that interference with the Insulin-like Growth Factor-1 Receptor (IGF-1R) signaling pathway reduces the proliferation of TC-71 cells [1]. Therefore TC-71 cells served as a positive control cell line for monitoring the activity of compounds against IGF-1R-mediated cell proliferation. In contrast, published data has demonstrated that the proliferation of HCT 116 cells is independent of IGF-1R signaling [2]. Therefore the HCT 116 cell line served as a negative control.

2000 TC-71 cells or 1000 HCT 116 cells were seeded per well in 180 μL IMDM+10% foetal calf serum (FCS)+ penicillin/streptomycin into 96-well microtitre plates. The plates were placed in a cell culture incubator (37° C. in a humidified atmosphere of 95% O₂/5 CO₂) overnight. The following day, serial dilutions of compounds, prepared in duplicates, were transferred onto the cell layers (controls without compound). The cells were cultivated for a further 72 h in the cell culture incubator. 20 μL of Alamar Blue™ (Serotec Ltd, Düsseldorf, Germany) was added to each well and the plates incubated for 7 h in the cell culture incubator. Fluorescence (extinction wavelength of 544 nm and emission at 590 nm) was then measured and the normalized data fitted by iterative calculation with a sigmoidal curve analysis program (Graph Pad Prism) with a variable Hill slope to determine the IC₅₀ values.

The EC₅₀ ranges of the following compounds were determined on TC-71 cells according to this assay (“+++”<50 nM; 50 nM<“++”<250 nM; 250 nM<“+”<3 μM):

EC₅₀ TC-71 # [nM] I-238 ++ I-31 +++ I-53 ++ I-54 ++ I-55 ++ I-56 + I-57 +++ I-66 + I-67 ++ I-68 +++ I-69 +++ I-291 ++ I-292 ++ I-293 ++ I-294 + I-295 ++ I-296 ++ I-297 ++ I-298 ++ I-299 +++ I-300 +++ I-97 +++ I-102 ++ I-103 +++ I-104 +++ I-160 + I-301 +++ I-302 +++ I-303 +++ I-304 +++ I-305 ++ I-306 +++ I-307 +++ I-308 +++ I-309 +++ I-310 ++ I-311 ++ I-312 ++ I-313 +++ I-314 ++ I-316 ++ I-317 +++ I-318 +++ I-319 +++ I-320 +++ I-321 +++ I-322 +++ I-323 +++ I-324 +++ I-325 ++ I-326 ++ I-327 +++ I-328 +++ I-329 +++ I-330 +++ I-331 +++ I-332 +++ I-333 + I-334 +++ I-335 +++ I-336 ++ I-337 + I-338 + I-339 +++ I-340 ++ I-341 +++ I-342 +++ I-203 + I-204 ++ I-208 ++ I-209 ++ I-210 +++ I-211 ++ I-212 ++ I-213 ++ I-214 +++ I-215 + I-216 ++ I-217 ++ I-218 +++ I-219 +++ I-220 ++ I-221 +++ I-350 +++ I-351 +++ I-352 +++ I-353 +++ I-354 +++ I-355 + I-356 +++ I-357 ++ I-358 +++ I-359 +++ I-360 +++ I-361 +++ I-362 +++ I-363 ++ I-364 +++ I-365 ++ I-366 ++ I-367 +++ I-368 +++ I-369 +++ I-370 +++ I-371 +++ I-372 +++ I-373 ++ I-374 ++ I-375 +++ I-376 +++ I-377 +++ I-378 ++ I-379 ++ I-380 ++ I-381 ++ I-382 +++ I-383 ++ I-384 ++ I-385 ++ I-386 +++ I-235 +

In addition to TC-71, several other cancer cell lines from diverse tissue origins, which have previously been demonstrated to be sensitive to IGF-1R inhibition, were shown to be sensitive to compounds (I). Examples include COLO 205 (colorectal cancer) [3], LP-1 (multiple myeloma) [4] and HL-60 (acute myeloid leukemia) [5].

REFERENCE LIST

-   1 Manara, M. C., Landuzzi, L., Nanni, P., Nicoletti, G., Zambelli,     D., Lollini, P. L., Nanni, C., Hofmann, F., Garcia-Echeverria, C.,     Picci, P. and Scotlandi, K. (2007) Preclinical in vivo study of new     insulin-like growth factor-I receptor—specific inhibitor in Ewing's     sarcoma. Clin. Cancer Res., 13, 1322-1330. -   2 Pitts, T. M., Tan, A. C., Kulikowski, G. N., Tentler, J. J.,     Brown, A. M., Flanigan, S. A., Leong, S., Coldren, C. D., Hirsch, F.     R., Varella-Garcia, M., Korch, C. and Eckhardt, S. G. (2010)     Development of an integrated genomic classifier for a novel agent in     colorectal cancer: approach to individualized therapy in early     development. Clin Cancer Res., 16, 3193-3204. -   3 Haluska, P., carboni, J. M., Loegering, D. A., Lee, F. Y.,     Wittman, M., Saulnier, M. G., to Frennesson, D. B., Kalli, K. R.,     Conover, C. A., Attar, R. M., Kaufmann, S. H., Gottardis, M. and     Erlichman, C. (2006) In vitro and in vivo antitumor effects of the     dual insulin-like growth factor-I/insulin receptor inhibitor,     BMS-554417. Cancer Res., 66, 362-371. -   4 Georgii-Hemming, P., Wiklund, H. J., Ljunggren, O. and     Nilsson, K. (1996) Insulin-like growth factor I is a growth and     survival factor in human multiple myeloma cell lines. Blood, 88,     2250-2258. -   5 Wahner Hendrickson, A. E., Haluska, P., Schneider, P. A.,     Loegering, D. A., Peterson, K. L., Attar, R., Smith, B. D.,     Erlichman, C., Gottardis, M., Karp, J. E., carboni, J. M. and     Kaufmann, S. H. (2009) Expression of insulin receptor isoform A and     insulin-like growth factor-1 receptor in human acute myelogenous     leukemia: effect of the dual-receptor inhibitor BMS-536924 in vitro.     Cancer Res., 69, 7635-7643.

On the basis of their biological properties the compounds of general formula (I) according to the invention, their tautomers, racemates, enantiomers, diastereomers, mixtures thereof and the salts of all the above-mentioned forms are suitable for treating diseases characterised by excessive or abnormal cell proliferation.

Such diseases include for example: viral infections (e.g. HIV and Kaposi's sarcoma); inflammatory and autoimmune diseases (e.g. colitis, arthritis, Alzheimer's disease, glomerulonephritis and wound healing); bacterial, fungal and/or parasitic infections; leukaemias, lymphomas and solid tumours (e.g. carcinomas and sarcomas), skin diseases (e.g. psoriasis); diseases based on hyperplasia which are characterised by an increase in the number of cells (e.g. fibroblasts, hepatocytes, bones and bone marrow cells, cartilage or smooth muscle cells or epithelial cells (e.g. endometrial hyperplasia)); bone diseases and cardiovascular diseases (e.g. restenosis and hypertrophy). They are also suitable for protecting proliferating cells (e.g. hair, intestinal, blood and progenitor cells) from DNA damage caused by radiation, UV treatment and/or cytostatic treatment.

For example, the following cancers may be treated with compounds according to the invention, without being restricted thereto: brain tumours such as for example acoustic neurinoma, astrocytomas such as pilocytic astrocytomas, fibrillary astrocytoma, protoplasmic astrocytoma, gemistocytary astrocytoma, anaplastic astrocytoma and glioblastoma, brain lymphomas, brain metastases, hypophyseal tumour such as prolactinoma, HGH (human growth hormone) producing tumour and ACTH producing tumour (adrenocorticotropic hormone), craniopharyngiomas, medulloblastomas, meningeomas and oligodendrogliomas; nerve tumours (neoplasms) such as e.g. tumours of the vegetative nervous system such as neuroblastoma sympathicum, ganglioneuroma, paraganglioma (pheochromocytoma, chromaffinoma) and glomus-caroticum tumour, tumours on the peripheral nervous system such as amputation neuroma, neurofibroma, neurinoma (neurilemmoma, Schwannoma) and malignant Schwannoma, as well as tumours of the central nervous system such as brain and bone marrow tumours; intestinal cancer such as for example carcinoma of the rectum, colon carcinoma, colorectal carcinoma, anal carcinoma, carcinoma of the large bowel, tumours of the small intestine and duodenum; eyelid tumours such as basalioma or basal cell carcinoma; pancreatic cancer or carcinoma of the pancreas; bladder cancer or carcinoma of the bladder; lung cancer (bronchial carcinoma) such as for example small-cell bronchial carcinomas (oat cell carcinomas) and non-small cell bronchial carcinomas (NSCLC) such as plate epithelial carcinomas, adenocarcinomas and large-cell bronchial carcinomas; breast cancer such as for example mammary carcinoma such as infiltrating ductal carcinoma, colloid carcinoma, lobular invasive carcinoma, tubular carcinoma, adenocystic carcinoma and papillary carcinoma; non-Hodgkin's lymphomas (NHL) such as for example Burkitt's lymphoma, low-malignancy non-Hodgkin's lymphomas (NHL) and mucosis fungoides; uterine cancer or endometrial carcinoma or corpus carcinoma; CUP syndrome (Cancer of Unknown Primary); ovarian cancer or ovarian carcinoma such as mucinous, endometrial or serous cancer; gall bladder cancer; bile duct cancer such as for example Klatskin tumour; testicular cancer such as for example seminomas and non-seminomas; lymphoma (lymphosarcoma) such as for example malignant lymphoma, Hodgkin's disease, non-Hodgkin's lymphomas (NHL) such as chronic lymphatic leukaemia, leukaemic reticuloendotheliosis, immunocytoma, plasmocytoma (multiple myeloma), immunoblastoma, Burkitt's lymphoma, T-zone mycosis fungoides, large-cell anaplastic lymphoblastoma and lymphoblastoma; laryngeal cancer such as for example tumours of the vocal cords, supraglottal, glottal and subglottal laryngeal tumours; bone cancer such as for example osteochondroma, chondroma, chondroblastoma, chondromyxoid fibroma, osteoma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, giant cell tumour, chondrosarcoma, osteosarcoma, Ewing's sarcoma, reticulo-sarcoma, plasmocytoma, fibrous dysplasia, juvenile bone cysts and aneurysmatic bone cysts; head and neck to tumours such as for example tumours of the lips, tongue, floor of the mouth, oral cavity, gums, palate, salivary glands, throat, nasal cavity, paranasal sinuses, larynx and middle ear; liver cancer such as for example liver cell carcinoma or hepatocellular carcinoma (HCC); leukaemias, such as for example acute leukaemias such as acute lymphatic/lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML); chronic leukaemias such as chronic lymphatic leukaemia (CLL), chronic myeloid leukaemia (CML); stomach cancer or gastric carcinoma such as for example papillary, tubular and mucinous adenocarcinoma, signet ring cell carcinoma, adenosquamous carcinoma, small-cell carcinoma and undifferentiated carcinoma; melanomas such as for example superficially spreading, nodular, lentigo-maligna and acral-lentiginous melanoma; renal cancer such as e.g. kidney cell carcinoma or hypernephroma or Grawitz's tumour; oesophageal cancer or carcinoma of the oesophagus; penile cancer; prostate cancer; throat cancer or carcinomas of the pharynx such as for example nasopharynx carcinomas, oropharynx carcinomas and hypopharynx carcinomas; retinoblastoma; vaginal cancer or vaginal carcinoma; plate epithelial carcinomas, adenocarcinomas, in situ carcinomas, malignant melanomas and sarcomas; thyroid carcinomas such as for example papillary, follicular and medullary thyroid carcinoma, as well as anaplastic carcinomas; spinalioma, epidormoid carcinoma and plate epithelial carcinoma of the skin; thymomas, cancer of the urethra and cancer of the vulva.

The new compounds may be used for the prevention, short-term or long-term treatment of the above-mentioned diseases, optionally also in combination with radiotherapy or other “state-of-the-art” compounds, such as e.g. cytostatic or cytotoxic substances, cell proliferation inhibitors, anti-angiogenic substances, steroids or antibodies.

The compounds of general formula (I) may be used on their own or in combination with other active substances according to the invention, optionally also in combination with other pharmacologically active substances.

Chemotherapeutic agents which may be administered in combination with the compounds according to the invention, include, without being restricted thereto, hormones, hormone analogues and antihormones (e.g. tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxy-progesterone, octreotide), aromatase inhibitors (e.g. anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane), LHRH agonists and antagonists (e.g. goserelin acetate, luprolide), inhibitors of growth factors (growth factors such as for example “platelet derived growth factor (PDGF)”, “fibroblast growth factor (FGF)”, “vascular endothelial growth factor (VEGF)”, “epidermal growth factor (EGF)”, “insuline-like growth factors (IGF)”, “human epidermal growth factor (HER, e.g. HER2, HER3, HER4)” and “hepatocyte growth factor (HGF)”), inhibitors are for example “growth factor” antibodies, “growth factor receptor” antibodies and tyrosine kinase inhibitors, such as for example cetuximab, gefitinib, imatinib, lapatinib and trastuzumab); antimetabolites (e.g. antifolates such as methotrexate, raltitrexed, pyrimidine analogues such as 5-fluorouracil, capecitabin and gemcitabin, purine and adenosine analogues such as mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine, fludarabine); antitumour antibiotics (e.g. anthracyclins such as doxorubicin, daunorubicin, epirubicin and idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin); platinum derivatives (e.g. cisplatin, oxaliplatin, carboplatin); alkylation agents (e.g. estramustin, meclorethamine, melphalan, chlorambucil, busulphan, dacarbazin, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas such as for example carmustin and lomustin, thiotepa); antimitotic agents (e.g. Vinca alkaloids such as for example vinblastine, vindesin, vinorelbin and vincristine; and taxanes such as paclitaxel, docetaxel); tubuline inhibitors; PARP inhibitors, topoisomerase inhibitors (e.g. epipodophyllotoxins such as for example etoposide and etopophos, teniposide, amsacrin, topotecan, irinotecan, mitoxantron), serine/threonine kinase inhibitors (e.g. PDK 1 inhibitors, B-Raf inhibitors, mTOR inhibitors, mTORC1 inhibitors, PI3K inhibitors, dual mTOR/PI3K inhibitors, STK 33 inhibitors, AKT inhibitors, PLK 1 inhibitors, inhibitors of CDKs, Aurora kinase inhibitors), tyrosine kinase inhibitors (e.g. PTK2/FAK inhibitors), protein protein interaction inhibitors (e.g. IAP, Mcl-1, MDM2/MDMX), MEK inhibitors, ERK inhibitors, IGF-1R inhibitors, ErbB receptor inhibitors, rapamycin analogs (e.g. everolimus, temsirolimus, ridaforolimus, sirolimus) and various chemotherapeutic agents such as amifostin, anagrelid, clodronat, filgrastin, interferon, interferon alpha, leucovorin, rituximab, procarbazine, levamisole, mesna, mitotane, pamidronate and porfimer.

Other possible combination partners are 2-chlorodesoxyadenosine, 2-fluorodesoxy-cytidine, 2-methoxyoestradiol, 2C4,3-alethine, 131-1-TM-601, 3CPA, 7-ethyl-10-hydroxycamptothecin, 16-aza-epothilone B, A 105972, A 204197, abiraterone, to aldesleukin, alitretinoin, allovectin-7, altretamine, alvocidib, amonafide, anthrapyrazole, AG-2037, AP-5280, apaziquone, apomine, aranose, arglabin, arzoxifene, atamestane, atrasentan, auristatin PE, AVLB, AZ10992, ABX-EGF, AMG-479 (ganitumab), ARRY 162, ARRY 438162, ARRY-300, ARRY-142886/AZD-6244 (selumetinib), ARRY-704/AZD-8330, AR-12, AR-42, AS-703988, AXL-1717, AZD-8055, AZD-5363, AZD-6244, ARQ-736, ARQ 680, AS-703026 (primasertib), avastin, AZD-2014, azacytidine, azaepothilone B, azonafide, BAY-43-9006, BAY 80-6946, BBR-3464, BBR-3576, bevacizumab, BEZ-235, biricodar dicitrate, BCX-1777, BKM-120, bleocin, BLP-25, BMS-184476, BMS-247550, BMS-188797, BMS-275291, BMS-663513, BMS-754807, BNP-1350, BNP-7787, BIBW 2992 (afatinib, tomtovok), BIBF 1120 (vargatef), BI 836845, B1 2536, BI 6727, BI 836845, BI 847325, BI 853520, BIIB-022, bleomycinic acid, bleomycin A, bleomycin B, brivanib, bryostatin-1, bortezomib, brostallicin, busulphan, BYL-719, CA-4 prodrug, CA-4, CapCell, calcitriol, canertinib, canfosfamide, capecitabine, carboxyphthalatoplatin, CCl-779, CC-115, CC-223, CEP-701, CEP-751, CBT-1 cefixime, ceflatonin, ceftriaxone, celecoxib, celmoleukin, cemadotin, CH4987655/RO-4987655, chlorotrianisene, cilengitide, ciclosporin, CDA-II, CDC-394, CKD-602, CKI-27, clofarabin, colchicin, combretastatin A4, COT inhibitors, CHS-828, CH-5132799, CLL-Thera, CMT-3 cryptophycin 52, CTP-37, CTLA-4 monoclonal antibodies, CP-461, CV-247, cyanomorpholinodoxorubicin, cytarabine, D 24851, decitabine, deoxorubicin, deoxyrubicin, deoxycoformycin, depsipeptide, desoxyepothilone B, dexamethasone, dexrazoxanet, diethylstilbestrol, diflomotecan, didox, DMDC, dolastatin 10, doranidazole, DS-7423, E7010, E-6201, edatrexat, edotreotide, efaproxiral, eflornithine, EGFR inhibitors, EKB-569, EKB-509, enzastaurin, elsamitrucin, epothilone B, epratuzumab, ER-86526, erlotinib, ET-18-OCH3, ethynylcytidine, ethynyloestradiol, exatecan, exatecan mesylate, exemestane, exisulind, fenretinide, figitumumab, floxuridine, folic acid, FOLFOX, FOLFOX4, FOLFIRI, formestane, fotemustine, galarubicin, gallium maltolate, gefinitib, gemtuzumab, gimatecan, glufosfamide, GCS-100, GDC-0623, GDC-0941 (pictrelisib), GDC-0980, GDC-0032, GDC-0068, GDC-0349, GDC-0879, G17DT immunogen, GMK, GPX-100, gp100-peptide vaccines, GSK-5126766, GSK-690693, GSK-1120212 (trametinib), GSK-2118436 (dabrafenib), GSK-2126458, GSK-2132231A, GSK-2334470, GSK-2110183, GSK-2141795, GW2016, granisetron, herceptine, hexamethylmelamine, histamine, homoharringtonine, hyaluronic acid, hydroxyurea, hydroxyprogesterone caproate, ibandronate, ibritumomab, idatrexate, idenestrol, IDN-5109, IGF-1R inhibitors, IMC-1C11, IMC-A12 (cixutumumab), immunol, indisulam, interferon alpha-2a, interferon alpha-2b, pegylated interferon alpha-2b, interleukin-2, INK-1117, INK-128, INSM-18, ionafarnib, ipilimumab, iproplatin, irofulven, isohomohalichondrin-B, isoflavone, isotretinoin, ixabepilone, JRX-2, JSF-154, J-107088, conjugated oestrogens, kahalid F, ketoconazole, KW-2170, KW-2450, lobaplatin, leflunomide, lenograstim, leuprolide, leuporelin, lexidronam, LGD-1550, linezolid, lutetium texaphyrin, lometrexol, losoxantrone, LU 223651, lurtotecan, LY-S6AKT1, LY-2780301, mafosfamide, marimastat, mechloroethamine, MEK inhibitors, MEK-162, methyltestosteron, methylprednisolone, MEDI-573, MEN-10755, MDX-H210, MDX-447, MDX-1379, MGV, midostaurin, minodronic acid, mitomycin, mivobulin, MK-2206, MK-0646 (dalotuzumab), MLN518, motexaf in gadolinium, MS-209, MS-275, MX6, neridronate, neratinib, Nexavar, neovastat, nilotinib, nimesulide, nitroglycerin, nolatrexed, norelin, N-acetylcysteine, 06-benzylguanine, oblimersen, omeprazole, oncophage, oncoVEX^(GM-CSF), ormiplatin, ortataxel, OX44 antibodies, OSI-027, OSI-906 (linsitinib), 4-1BB antibodies, oxantrazole, oestrogen, panitumumab, patupilone, pegfilgrastim, PCK-3145, pegfilgrastim, PBI-1402, PBI-05204, PDO325901, PD-1 antibodies, PEG-paclitaxel, albumin-stabilized paclitaxel, PEP-005, PF-05197281, PF-05212384, PF-04691502, PHT-427, P-04, PKC412, P54, P1-88, pelitinib, pemetrexed, pentrix, perifosine, perillylalcohol, pertuzumab, PI3K inhibitors, PI3K/mTOR inhibitors, PG-TXL, PG2, PLX-4032/R0-5185426 (vemurafenib), PLX-3603/R0-5212054, PT-100, PWT-33597, PX-866, picoplatin, pivaloyloxymethylbutyrate, pixantrone, phenoxodiol 0, PKI166, plevitrexed, plicamycin, polyprenic acid, porfiromycin, prednisone, prednisolone, quinamed, quinupristin, R115777, RAF-265, ramosetron, ranpirnase, RDEA-119/BAY 869766, RDEA-436, rebeccamycin analogues, receptor tyrosine kinase (RTK) inhibitors, revimid, RG-7167, RG-7304, RG-7421, RG-7321, RG 7440, rhizoxin, rhu-MAb, rinfabate, risedronate, rituximab, robatumumab, rofecoxib, RO-31-7453, RO-5126766, RO-5068760, RPR 109881A, rubidazone, rubitecan, R-flurbiprofen, RX-0201, S-9788, sabarubicin, SAHA, sargramostim, satraplatin, SB 408075, Se-015/Ve-015, SU5416, SU6668, SDX-101, semustin, seocalcitol, SM-11355, SN-38, SN-4071, SR-27897, SR-31747, SR-13668, SRL-172, sorafenib, spiroplatin, squalamine, suberanilohydroxamic acid, sutent, T 900607, T 138067, TAK-733, TAS-103, tacedinaline, talaporf in, Tarceva, tariquitar, tasisulam, taxotere, taxoprexin, tazarotene, tegafur, temozolamide, tesmilifene, testosterone, testosterone propionate, tesmilifene, tetraplatin, tetrodotoxin, tezacitabine, thalidomide, theralux, therarubicin, thymalfasin, thymectacin, tiazofurin, tipifarnib, tirapazamine, tocladesine, tomudex, toremofin, trabectedin, TransMID-107, transretinic acid, traszutumab, tremelimumab, tretinoin, triacetyluridine, triapine, triciribine, trimetrexate, TLK-286TXD 258, tykerb/tyverb, urocidin, valrubicin, vatalanib, vincristine, vinflunine, virulizin, WX-UK1, WX-554, vectibix, xeloda, XELOX, XL-147, XL-228, XL-281, XL-518/R-7420/GDC-0973, XL-765, YM-511, YM-598, ZD-4190, ZD-6474, ZD-4054, ZD-0473, ZD-6126, ZD-9331, ZD1839, ZSTK-474, zoledronat and zosuquidar.

Suitable preparations include for example tablets, capsules, suppositories, solutions-particularly solutions for injection (s.c., i.v., i.m.) and infusion—elixirs, emulsions or dispersible powders. The content of the pharmaceutically active compound(s) should be in the range from 0.1 to 90 wt.-%, preferably 0.5 to 50 wt.-% of the composition as a whole, i.e. in amounts which are sufficient to achieve the dosage range specified below. The doses specified may, if necessary, be given several times a day.

Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers.

Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly the tablet coating may consist of a number of layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.

Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.

Solutions for injection and infusion are prepared in the usual way, e.g. with the addition of isotonic agents, preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid, optionally using emulsifiers and/or dispersants, whilst if water is used as the diluent, for example, organic solvents may optionally be used as solvating agents or dissolving aids, and transferred into injection vials or ampoules or infusion bottles.

Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules.

Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof.

Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose) emulsifiers (e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate).

The preparations are administered by the usual methods, preferably by oral or transdermal route, most preferably by oral route. For oral administration the tablets may, of course contain, apart from the abovementioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatine and the like. Moreover, lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used at the same time for the tabletting process. In the case of aqueous suspensions the active substances may be combined with various flavour enhancers or colourings in addition to the excipients mentioned above.

For parenteral use, solutions of the active substances with suitable liquid carriers may be used.

The dosage for intravenous use is from 1-1000 mg per hour, preferably between 5 and 500 mg per hour.

However, it may sometimes be necessary to depart from the amounts specified, depending on the body weight, the route of administration, the individual response to the drug, the nature of its formulation and the time or interval over which the drug is administered. Thus, in some cases it may be sufficient to use less than the minimum dose given above, whereas in other cases the upper limit may have to be exceeded. When administering large amounts it may be advisable to divide them up into a number of smaller doses spread over the day.

The formulation examples which follow illustrate the present invention without restricting its scope:

Examples of Pharmaceutical Formulations

A) Tablets per tablet active substance according to formula (I) 100 mg lactose 140 mg corn starch 240 mg polyvinylpyrrolidone 15 mg magnesium stearate 5 mg 500 mg

The finely ground active substance, lactose and some of the corn starch are mixed together. The mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried. The granules, the remaining corn starch and the magnesium stearate are screened and mixed together. The mixture is compressed to produce tablets of suitable shape and size.

B) Tablets per tablet active substance according to formula (I) 80 mg lactose 55 mg corn starch 190 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mg sodium-carboxymethyl starch 23 mg magnesium stearate 2 mg 400 mg

The finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the remaining corn starch and water to form a granulate which is dried and screened. The sodiumcarboxymethyl starch and the magnesium stearate are added and mixed in and the mixture is compressed to form tablets of a suitable size.

C) Ampoule solution active substance according to formula (I) 50 mg sodium chloride 50 mg water for inj. 5 ml

The active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. The solution obtained is filtered free from pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterilised and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50 mg of active substance. 

The invention claimed is:
 1. A compound of the formula (I)

wherein R⁵ is selected from among trifluoromethyl and halogen; R⁶, R⁷ and R⁸ are independently selected in each case from among hydrogen and C₁₋₄alkyl or R⁶ and R⁷ together with the carbon atom to which they bond form a saturated, 3-5 membered hydrocarbon ring; ring system A is selected from among C₆₋₁₀aryl, 3-14 membered heterocyclyl and 5-12 membered heteroaryl; each R⁹ is independently selected in each case from among C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, halogen and —CN; m denotes 0, 1, 2 or 3; L¹ is selected from among a bond, —(CH₂)_(n)—O, —(CH₂)_(n)—NH, —(CH₂)_(n)—NH—C(O), —(CH₂)_(n)—C(O)—NH, —(CH₂)_(n)— and —(CH₂)_(n)—C(O), while in the present nomenclature the linker group L¹ on the right binds to the ring system A; n denotes 0, 1, 2 or 3; ring system B is selected from among 4-10 membered, saturated or unsaturated heterocyclyl and phenyl; each R¹⁰ is independently selected in each case from among R^(a) and R^(b); p denotes 0, 1, 2 or 3; each R^(a) independently denotes a group optionally substituted by one or more identical or different R^(b) and/or R^(c) selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl; each R^(b) is independently selected in each case from among —OR^(c), —SR^(c), —NR^(c)R^(c), halogen, —CN, —NO₂, —C(O)R^(c), —C(O)OR^(c), —C(O)NR^(c)R^(c), —C(NR^(f))NR^(c)R^(c), —OC(O)R^(c), —OC(O)OR^(c), —S(O)₂R^(c), —S(O)₂NR^(c)R^(c), —NR^(f)C(O)R^(c), —NR^(f)C(O)OR^(c), —NR^(f)C(O)NR^(c)R^(c), —NR^(f)C(NR^(f))NR^(c)R^(c) and —NR^(f)S(O)₂R^(c), as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems; each R^(c) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(d) and/or R^(e) selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl; each R^(d) is independently selected in each case from among —OR^(e), —SR^(e), —NR^(e)R^(e), halogen, —CN, —NO₂, —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(e)R^(e), —C(NR^(f))NR^(e)R^(e), —OC(O)R^(e), —OC(O)OR^(e), —S(O)₂R^(e), —S(O)₂NR^(e)R^(e), —NR^(f)C(O)R^(e), —NR^(f)C(O)OR^(e), —NR^(f)C(O)NR^(e)R^(e), —NR^(f)C(NR^(f))NR^(e)R^(e) and —NR^(f)S(O)₂R^(e), as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems; each R^(e) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(f) selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl, and each R^(f) is independently selected in each case from among hydrogen and C₁₋₆alkyl, while the compounds (I) may optionally also occur in the form of their tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or as the respective salts of all the above-mentioned forms.
 2. The compound according to claim 1, wherein R⁵ denotes trifluoromethyl.
 3. The compound according to claim 1, wherein R⁵ denotes chlorine.
 4. The compound according to claim 1, wherein R⁵ denotes bromine.
 5. The compound according to claim 1, wherein R⁶ and R⁷ in each case denote methyl and R⁸ denotes hydrogen.
 6. The compound according to claim 1, wherein R⁶, R⁷ and R⁸ in each case denote hydrogen.
 7. The compound according to claim 1, wherein R⁶ and R⁷ together with the carbon atom to which they bond form a cyclopropyl ring and R⁸ denotes hydrogen.
 8. The compound according to claim 1, wherein ring system A is selected from among phenyl and 5-6 membered heteroaryl.
 9. The compound according to claim 8, wherein ring system A is a phenyl.
 10. The compound according to claim 8, wherein ring system A is a 5-6 membered, nitrogen-containing heteroaryl.
 11. The compound according to claim 10, wherein ring system A is a pyridyl or pyrazolyl.
 12. The compound according to claim 1, wherein m has the value
 0. 13. The compound according to claim 1, wherein m has the value 1 or 2 and R⁹ is selected from among halogen, C₁₋₄alkyl and C₁₋₄alkoxy.
 14. The compound according to claim 13, wherein m has the value 1 or 2 and R⁹ is selected from among C₁₋₄alkyl and C₁₋₄alkoxy.
 15. The compound according to claim 14, wherein m has the value 1 or 2 and R⁹ is selected from among methyl, ethyl, methoxy and ethoxy.
 16. The compound according to claim 1, wherein ring system A and the m groups R⁹ together denote

R^(9a) is selected from among hydrogen, C₁₋₄alkyl and C₁₋₄alkoxy and R^(9b) is selected from among hydrogen and C₁₋₄alkyl.
 17. The compound according to claim 16, wherein ring system A and the m groups R⁹ together denote

R^(9a) is selected from among hydrogen, methyl, ethyl, methoxy and ethoxy and R^(9b) is selected from among hydrogen, methyl and ethyl.
 18. The compound according to claim 1, wherein ring system A and the m groups R⁹ together denote


19. The compound according to claim 1, wherein L¹ is selected from among a bond, —(CH₂)₂—O, —NH—C(O), —C(O)—NH— and —C(O), while in the present nomenclature the linker group L¹ on the right binds to the ring system A.
 20. The compound according to claim 19, wherein L¹ corresponds to a bond.
 21. The compound according to claim 19, wherein L¹ is selected from among —(CH₂)₂—O, —NH—C(O)— and —C(O)—.
 22. The compound according to claim 1, wherein ring system B is a 4-10 membered, saturated or unsaturated heterocyclyl.
 23. The compound according to claim 22, wherein ring system B is a 5-7 membered, saturated and nitrogen-containing heterocyclyl.
 24. The compound according to claim 23, wherein ring system B is selected from among piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl and 2,5-diaza-bicyclo[2,2,1]heptyl.
 25. The compound according to claim 1, wherein p has the value
 0. 26. The compound according to claim 1, wherein p has the value 1 or 2, each R¹⁰ is independently selected in each case from among R^(a) and R^(b); each R^(a) independently denotes a group optionally substituted by one or more identical or different R^(b) and/or R^(c) selected from among C₁₋₆alkyl, C₃₋₁₀cycloalkyl and 3-14 membered heterocyclyl; each R^(b) is independently selected in each case from among —OR^(c), —NR^(c)R^(c), halogen, —CN, —C(O)R^(c), —C(O)OR^(c), —C(O)NR^(c)R^(c), —S(O)₂R^(c) and —S(O)₂NR^(c)R^(c), as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems; each R^(c) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(d) and/or R^(e) selected from among C₁₋₆alkyl, C₃₋₁₀cycloalkyl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl; each R^(d) is independently selected in each case from among —OR^(e), —NR^(e)R^(e), —CN, —C(O)R^(e), —C(O)OR^(e) and —NR^(f)C(O)OR^(e), as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems; each R^(e) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(f) selected from among C₁₋₆alkyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl, and each R^(f) is independently selected in each case from among hydrogen and C₁₋₆alkyl.
 27. The compound according to claim 1, wherein p has the value 1 or 2, each R¹⁰ is independently selected in each case from among R^(a) and R^(b); each R^(a) independently denotes a group optionally substituted by one or more identical or different R^(b) and/or R^(c) selected from among C₁₋₆alkyl, C₃₋₆cycloalkyl and 4-7 membered heterocyclyl; each R^(b) is independently selected in each case from among —OR^(c), —NR^(c)R^(c), halogen, —CN, —C(O)R^(c), —C(O)OR^(c), —C(O)NR^(c)R^(c), —S(O)₂R^(c) and —S(O)₂NR^(c)R^(c), as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems; each R^(c) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(d) and/or R^(e) selected from among C₁₋₆alkyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocyclyl; each R^(d) is independently selected in each case from among —OR^(e), —NR^(e)R^(e), —CN, —C(O)R^(e), —C(O)OR^(e) and —NR^(f)C(O)OR^(e), as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems; each R^(e) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(f) selected from among C₁₋₆alkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocyclyl, and each R^(f) is independently selected in each case from among hydrogen and C₁₋₆alkyl.
 28. The compound according to one of claims 1, 26 or 27, wherein p has the value
 1. 29. The compound according to claim 1, wherein ring system B and the p groups R¹⁰ together denote

each R¹⁰ is independently selected in each case from among R^(a) and R^(b); each R^(a) independently denotes a group optionally substituted by one or more identical or different R^(b) and/or R^(c) selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl; each R^(b) is independently selected in each case from among —OR^(c), —SR^(c), —NR^(c)R^(c), halogen, —CN, —NO₂, —C(O)R^(c), —C(O)OR^(c), —C(O)NR^(c)R^(c), —C(NR^(f))NR^(c)R^(c), —OC(O)R^(c), —OC(O)OR^(c), —S(O)₂R^(c), —S(O)₂NR^(c)R^(c), —NR^(f)C(O)R^(c), —NR^(f)C(O)OR^(c), —NR^(f)C(O)NR^(c)R^(c), —NR^(f)C(NR^(f))NR^(c)R^(c) and —NR^(f)S(O)₂R^(c), as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems; each R^(c) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(d) and/or R^(e) selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl; each R^(d) is independently selected in each case from among —OR^(e), —SR^(e), —NR^(e)R^(e), halogen, —CN, —NO₂, —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(e)R^(e), —C(NR^(f))NR^(e)R^(e), —OC(O)R^(e), —OC(O)OR^(e), —S(O)₂R^(e), —S(O)₂NR^(e)R^(e), —NR^(f)C(O)R^(e), —NR^(f)C(O)OR^(e), —NR^(f)C(O)NR^(e)R^(e), —NR^(f)C(NR^(f))NR^(e)R^(e) and —NR^(f)S(O)₂R^(e), as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems; each R^(e) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(f) selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl, and each R^(f) is independently selected in each case from among hydrogen and C₁₋₆alkyl.
 30. The compound according to claim 29, wherein ring system B and the p groups R¹⁰ together denote

each R¹⁰ is independently selected in each case from among R^(a) and R^(b); each R^(a) independently denotes a group optionally substituted by one or more identical or different R^(b) and/or R^(c) selected from among C₁₋₆alkyl, C₃₋₁₀cycloalkyl and 3-14 membered heterocyclyl; each R^(b) is independently selected in each case from among —OR^(c), —NR^(c)R^(c), halogen, —CN, —C(O)R^(c), —C(O)OR^(c), —C(O)NR^(c)R^(c), —S(O)₂R^(c) and —S(O)₂NR^(c)R^(c), as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems; each R^(c) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(d) and/or R^(e) selected from among C₁₋₆alkyl, C₃₋₁₀cycloalkyl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl; each R^(d) is independently selected in each case from among —OR^(e), —NR^(e)R^(e), —CN, —C(O)R^(e), —C(O)OR^(e) and —NR^(f)C(O)OR^(e), as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems; each R^(e) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(f) selected from among C₁₋₆alkyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl, and each R^(f) is independently selected in each case from among hydrogen and C₁₋₆alkyl.
 31. The compound according to claim 30, wherein ring system B and the p groups R¹⁰ together denote

each R¹⁰ is independently selected in each case from among R^(a) and R^(b); each R^(a) independently denotes a group optionally substituted by one or more identical or different R^(b) and/or R^(c) selected from among C₁₋₆alkyl, C₃₋₆cycloalkyl and 4-7 membered heterocyclyl; each R^(b) is independently selected in each case from among —OR^(c), —NR^(c)R^(c), halogen, —CN, —C(O)R^(c), —C(O)OR^(c), —C(O)NR^(c)R^(c), —S(O)₂R^(c) and —S(O)₂NR^(c)R^(c), as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems; each R^(c) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(d) and/or R^(e) selected from among C₁₋₆alkyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocyclyl; each R^(d) is independently selected in each case from among —OR^(e), —NR^(e)R^(e), —CN, —C(O)R^(e), —C(O)OR^(e) and —NR^(f)C(O)OR^(e), as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems; each R^(e) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(f) selected from among C₁₋₆alkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocyclyl, and each R^(f) is independently selected in each case from among hydrogen and C₁₋₆alkyl.
 32. The compound according to claim 1, wherein ring system B and the p groups R¹⁰ together denote

each R¹⁰ is independently selected in each case from among —C(O)—C₁₋₄alkyl, hydrogen, C₁₋₆alkyl (CN), C₁₋₆haloalkyl —C(O)—O—C₁₋₄alkyl, —COOH, (C₁₋₄alkyl)₂N—C₁₋₄alkylene-C(O), (C₁₋₄alkyl)NH—C₁₋₄alkylene-C(O), H₂N—C₁₋₄alkylene-C(O), HO—C₁₋₄alkylene-C(O), —C(O)—N(C₁₋₄alkyl)₂, —C(O)—NH(C₁₋₄alkyl), —C(O)NH₂, C₁₋₄alkyl-O—C₁₋₄alkylene-C(O), 4-6 membered heterocyclyl (optionally substituted by C₁₋₄alkyl, C₃₋₆cycloalkyl or 3-6 membered heterocyclyl), C₃₋₆cycloalkyl, C₃₋₆cycloalkyl-C₁₋₄alkyl, HO—C₂₋₄alkyl, C₁₋₄alkyl-O—C₂₋₄alkyl, HO—C₂₋₄haloalkyl, C₁₋₄alkyl-S(O)₂, C₁₋₄alkyl-NH—C(O)—C₁₋₄alkyl, H₂N—C(O)—C₁₋₄alkyl and C₁₋₄alkyl-S(O)₂—C₁₋₄alkyl.
 33. The compound according to claim 32, wherein ring system B and the p groups R¹⁰ together denote


34. The compound according to claim 1, wherein ring system B and the p groups R¹⁰ together denote

each R¹⁰ is independently selected in each case from among C₁₋₄alkyl-O—C₂₋₄alkylene-NH, C₁₋₄alkyl-O—C₂₋₄alkylene-N(C₁₋₄alkyl), HO—C₂₋₄alkylene-N(C₁₋₄alkyl), HO—C₂₋₄alkylene-NH, 4-6 membered heterocyclyl (optionally substituted by C₁₋₄alkyl, 3-6 membered heterocyclyl, halogen, —OH, —CN, C₁₋₄alkoxy, —N(C₁₋₄alkyl)₂ or C₃₋₆cycloalkyl), (C₁₋₄alkyl)₂N—C₂₋₄alkylene-N(C₁₋₄alkyl), (C₁₋₄alkyl)₂N—C₂₋₄alkylene-NH, —N(C₁₋₄alkyl)₂, —NH(C₁₋₄alkyl), C₁₋₄ alkyl-NH—C(O)— and (C₁₋₄alkyl)₂N—C(O)—.
 35. A compound, or pharmaceutically acceptable salts thereof, selected from among:


36. The compound according to claim 1 wherein the compound is a pharmaceutically acceptable salt thereof.
 37. A method of treating a cancer selected from hepatocellular carcinomas (HCC), non-small cell lung cancer (NSCLC), breast cancer and prostate cancer comprising administering to a patient a therapeutically effective amount of a compound according to claim 1 or the pharmaceutically acceptable salts thereof.
 38. The method according to claim 37 wherein the patient is a human being.
 39. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 or the pharmaceutically acceptable salts thereof optionally in combination with conventional excipients and/or carriers.
 40. The pharmaceutical composition according to claim 39 and at least one other cytostatic or cytotoxic active substance, different from formula (I) of claim
 1. 